記述言語：英語   掲載種別：研究論文（学術雑誌）  

Haploidentical haematopoietic cell transplantation (haplo-HCT) using post-transplant cyclophosphamide (PTCY) as graft-versus-host disease (GVHD) prophylaxis is the standard of care for various haematological malignancies. The original PTCY dose after haplo-HCT was 100 mg/kg, but no dose-finding studies have been performed to identify the optimal dose. We performed a retrospective analysis to compare standard-dose PTCY (100 mg/kg) with reduced-dose PTCY (80 mg/kg): 969 in the standard-dose group and 538 in the reduced-dose group. As there was a significant difference between the two groups regarding patient and transplant characteristics, we performed propensity score (PS) matching. After PS matching, 425 patients in each group were included. The probabilities of 2-year OS were 55.9% in the standard-dose group and 47.0% in the reduced-dose group (p = 0.36). The cumulative incidences of 2-year non-relapse mortality were 21.3% in the standard-dose group and 20.5% in the reduced-dose group (p = 0.55). There was no significant difference in the incidence of acute (grade II-IV 29.2% [95% CI, 24.9-33.6] vs. 25.3% [95% CI, 21.3-29.6]; grade III-IV 7.3% [95% CI, 5.1-10.0] vs. 6.6% [95% CI, 4.5-9.3]) or chronic GVHD. In conclusion, reduced- and standard-dose PTCY were comparable in terms of major clinical outcomes.

DOI： 10.1111/bjh.19228

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

There is limited evidence regarding the association between graft-versus-host disease (GVHD) and reduced relapse in patients who undergo allogeneic hematopoietic stem cell transplantation from haploidentical donors (haplo-HSCT) using post-transplant cyclophosphamide (PTCY). We investigated the association between GVHD and transplant outcomes in 938 patients who received haplo-HSCT using PTCY. Overall survival (OS), relapse rate, and non-relapse mortality (NRM) were evaluated using landmark analysis at the landmark points at 100 and 360 days after HSCT for acute and chronic GVHD, respectively. Grade I-II acute GVHD was not associated with OS (adjusted hazard ratio: 1.15, 95% confidence interval: 0.85-1.57), relapse (1.03, 0.74-1.45) and NRM (1.15, 0.74-1.77). Conversely, grade III-IV acute GVHD was associated with higher NRM (3.16, 1.61-6.19), but no other outcomes. Limited chronic GVHD was not associated with OS (1.11, 0.48-1.95), relapse (1.05, 0.30-3.75) and NRM (1.30, 0.45-3.79). Extensive chronic GVHD was associated with higher NRM (2.40, 1.03-5.57), but no other outcome. In conclusion, any GVHD was not associated with a reduced relapse rate and improved OS, and Grade III-IV acute GVHD and extensive chronic GVHD were associated with higher NRM in patients who received haplo-HSCT using PTCY.

DOI： 10.1038/s41409-023-02142-w

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Large-volume leukapheresis (LVL) refers to processing of more than three volumes of blood in a single session for peripheral blood stem cell collection. Recently, continuous mononuclear cell collection (cMNC) protocol has been developed using the Spectra Optia system, which is a widely used apheresis device. LVL using the novel protocol has been investigated in patients. However, the efficiency and safety of LVL in healthy donors using this protocol has not been characterized. Therefore, this study aimed to evaluate the efficiency and tolerability of CD34+ collection of LVL with the cMNC protocol in healthy donors. STUDY DESIGN AND METHODS: We retrospectively collected data on LVL (>3 total blood volume) and normal-volume leukapheresis (NVL) performed in healthy donors between October 2019 and December 2021. All procedures were performed using the cMNC protocol. RESULTS: Although pre-apheresis CD34+ cell count was lesser in LVL (23.5 vs. 58.0/μL, p < .001), CD34+ collection efficiency was comparable between LVL and NVL (61.2% vs. 61.4%, p = .966). Platelet loss was significantly higher in LVL compared to NVL (38.0% vs. 29.4%, p < .001), with no correlation between attrition of platelet and processing blood volume. Moreover, the incidence of citrate toxicity during procedures was comparable between the two groups (31.6% vs. 21.4%, p = .322). All LVL procedures could be completed without any adverse events. CONCLUSION: Allogeneic LVL procedure using Spectra Optia cMNC protocol was well tolerated by the donors and resulted in efficient collection of CD34+ cells, which was comparable to that of NVL.

DOI： 10.1111/trf.17563

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記述言語：日本語   出版者・発行元：(一社)日本造血・免疫細胞療法学会  

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記述言語：英語   出版者・発行元：(一社)日本血液学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The distribution and clinical impact of cell-of-origin (COO) subtypes of diffuse large B-cell lymphoma (DLBCL) outside Western countries remain unknown. Recent literature also suggests that there is an additional COO subtype associated with the germinal center dark zone, that warrants wider validation to generalize clinical relevance. Here, we assembled a cohort of Japanese patients with untreated DLBCL and determined the refined COO subtypes, that include the dark zone signature (DZsig), using the NanoString DLBCL90 assay. To compare the distribution and clinical characteristics of the molecular subtypes, we used a dataset from the cohort of BC Cancer (BCC) (n = 804). Of the 1050 patients where DLBCL90 assay was successfully performed in our cohort, 35%, 45%, and 6% of patients were identified to be germinal center B-cell-like (GCB)-DLBCL, activated B-cell-like (ABC)-DLBCL, and DZsigpos-DLBCL, respectively, with the highest prevalence of ABC-DLBCL differing significantly from that of BCC (P < 0.001). GCB-DLBCL, ABC-DLBCL, and DZsigpos-DLBCL were associated with two-year overall survival rates of 88%, 75%, and 66%, respectively (P < 0.0001), with patients of the DZsigpos-DLBCL having the poorest prognosis. In contrast, GCB-DLBCL without DZsig showed excellent outcomes following rituximab-containing immunochemotherapy. DZsigpos-DLBCL was associated with the significant enrichment of tumors with CD10 expression, concurrent MYC/BCL2 expression, and depletion of microenvironmental components (all P < 0.05). These results provide evidence of the distinct distribution of clinically relevant molecular subtypes in Japanese DLBCL and that refined COO, as measured by the DLBCL90 assay, is a robust prognostic biomarker that is consistent across geographical areas.

DOI： 10.1182/bloodadvances.2023010402

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The feasibility of lymphocyte isolation and flow cytometry using a single endoscopic biopsy specimen from the gastrointestinal tract of patients who have undergone hematopoietic stem cell transplantation has not been investigated. We acquired 51 endoscopic biopsy specimens from the gastrointestinal tract of 35 patients. We divided the flow cytometry samples into two groups: group A, successful lymphocyte isolation (n=24), and group B, incomplete isolation (n=27). We compared the backgrounds of the samples between the groups to reveal crucial elements in the successful isolation of lymphocytes residing in the gastrointestinal tract. Comparison between the groups revealed lymphocyte isolation success rates differed between biopsy sites. Isolation was most successful in samples from the duodenum (8/9, 88.9%), followed by the ileum (4/8, 50.0%), large intestine (4/11, 36.4%), and stomach (8/23, 34.8%). Tacrolimus was used more frequently in group B (92.6%) than in group A (62.5%) (p=0.015). Logistic regression analysis revealed that isolation from the duodenum or ileum was a significant factor for successful isolation, while tacrolimus use was not statistically significant. In conclusion, the duodenum and ileum are more suitable sites than the stomach and colorectum for acquiring samples for flow cytometry.

DOI： 10.18926/AMO/65740

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The prognostic impact of corticosteroid therapy in patients receiving tisagenlecleucel (tisa-cel) treatment who are more likely to develop cytokine release syndrome (CRS) remains unclear. This study aimed to evaluate the clinical impact and lymphocyte kinetics of corticosteroid administration for CRS in 45 patients with relapsed and/or refractory B-cell lymphoma treated with tisa-cel. This was a retrospective evaluation of all consecutive patients diagnosed with relapsed and/or refractory diffuse large B-cell lymphoma, follicular lymphoma with histologic transformation to large B-cell lymphoma, or follicular lymphoma who received commercial-based tisa-cel treatment. The best overall response rate, complete response rate, median progression-free survival (PFS), and median overall survival (OS) were 72.7%, 45.5%, 6.6 months, and 15.3 months, respectively. CRS (predominantly grade 1/2) occurred in 40 patients (88.9%), and immune effector cell-associated neurotoxicity syndrome (ICANS) of all grades occurred in 3 patients (6.7%). No grade ≥3 ICANS occurred. Patients with high-dose (≥524 mg, methylprednisolone equivalent; n = 12) or long-term (≥8 days; n = 9) corticosteroid use had inferior PFS and OS to patients with low-dose or no corticosteroid use (both P < .05). The prognostic impact remained even in 23 patients with stable disease (SD) or progressive disease (PD) before tisa-cel infusion (P = .015). but not in patients with better disease status (P = .71). The timing of corticosteroid initiation did not have a prognostic impact. Multivariate analysis identified high-dose corticosteroid use and long-term corticosteroid use as independent prognostic factors for PFS and OS, respectively, after adjusting for elevated lactate dehydrogenase level before lymphodepletion chemotherapy and disease status (SD or PD). Lymphocyte kinetics analysis demonstrated that after methylprednisolone administration, the proportions of regulatory T cells (Tregs), CD4+ central memory T (TCM) cells, and natural killer (NK) cells were decreased, whereas the proportion of CD4+ effector memory T (TEM) cells was increased. Patients with a higher proportion of Tregs at day 7 had a lower incidence of CRS, but this did not affect prognosis, indicating that early elevation of Tregs may serve as a biomarker for CRS development. Furthermore, patients with higher numbers of CD4+ TCM cells and NK cells at various time points had significantly better PFS and OS, whereas the number of CD4+ TEM cells did not impact prognostic outcomes. This study suggests that high-dose or long-term corticosteroid use attenuates the efficacy of tisa-cel, especially in patients with SD or PD. Additionally, patients with high levels of CD4+ TCM cells and NK cells after tisa-cel infusion had longer PFS and OS.

DOI： 10.1016/j.jtct.2023.06.018

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Granulocyte transfusion therapy is a rational therapeutic option for patients with prolonged, severe neutropenia. Although high molecular weight hydroxyethyl starch (hHES) facilitates the separation of red blood cells during granulocyte collection, renal dysfunction has been noted as a potential side effect. HES130/0.4 (Voluven®) is a medium molecular weight HES (mHES) with superior safety profiles compared to hHES. Although HES130/0.4 is reportedly effective in the collection of granulocytes, we lack studies comparing the efficiency of granulocyte collection using HES130/0.4 and hHES. STUDY DESIGN AND METHODS: We retrospectively collected the data from 60 consecutive apheresis procedures performed on 40 healthy donors at the Okayama University Hospital between July 2013 and December 2021. All procedures were performed using the Spectra Optia system. Based on the HES130/0.4 concentration in the separation chamber, granulocyte collection methods using HES130/0.4 were classified into m0.46, m0.44, m0.37, and m0.8 groups. We used HES130/0.4 and hHES groups to compare the various sample collection methods. RESULTS: The median granulocyte collection efficiency (CE) was approximately 24.0% and 28.1% in the m0.8 and hHES groups, respectively, which were significantly higher than those in the m0.46, m0.44, and m0.37 groups. One month following granulocyte collection with HES130/0.4, no significant changes were observed in serum creatinine levels compared to those before the donation. CONCLUSION: Therefore, we propose a granulocyte collection approach employing HES130/0.4, which is comparable to the use of hHES in terms of the granulocyte CE. A high concentration of HES130/0.4 in the separation chamber was considered crucial for granulocyte collection.

DOI： 10.1111/trf.17450

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記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

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記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Human leukocyte antigen (HLA)-matched sibling donors (MSDs) are the preferred choice for allogeneic hematopoietic cell transplantation (HCT). However, as myelodysplastic syndrome (MDS) is most frequently diagnosed in the elderly, MSDs are also likely to be of advanced age. It is unclear whether an MSD should be considered the primary choice for allogeneic HCT in elderly patients with MDS. We retrospectively compared survival and other outcomes in 1787 patients with MDS over 50 years of age and receiving allogeneic HCT between 2014 and 2020, using either MSD (n = 214), 8/8 allele-matched unrelated donor (MUD) (n = 562), 7/8 allele-MUD (n = 334), or unrelated cord blood (UCB) (n = 677) in Japan. In multivariate analysis, compared to MSD transplants, the risk of relapse was significantly lower following 8/8MUD transplants (hazard ratio [HR], 0.74; P = 0.047), whereas non-relapse mortality was significantly higher following UCB transplants (HR, 1.43; P = 0.041). However, donor type did not determine overall survival, disease-free survival, or graft-versus-host disease (GVHD)-free, relapse-free survival, but chronic GVHD-free, relapse-free survival was better after UCB (HR, 0.80; P = 0.025) and 8/8MUD (HR, 0.81; P = 0.032) compared to MSD transplants. Our study demonstrated that MSDs are not superior to alternative HCT methods, such as 8/8MUD, 7/8MUD, or UCB, in this population.

DOI： 10.1038/s41409-023-01997-3

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Allogeneic hematopoietic cell transplantation between female donors and male recipients (female-to-male allo-HCT) is a well-established risk factor for inferior survival outcomes due to a higher incidence of graft-versus-host disease (GVHD). However, a clinical significance of anti-thymocyte globulin (ATG) in the female-to-male allo-HCT has not been elucidated. In this study, we retrospectively evaluated male patients who underwent allo-HCT between 2012 and 2019 in Japan. In the female-to-male allo-HCT cohort (n = 828), the use of ATG was not associated with a decreased risk of GVHD (HR of acute GVHD 0.691 [95% CI: 0.461–1.04], P = 0.074; HR of chronic GVHD 1.06 [95% CI: 0.738–1.52], P = 0.76), but was associated with favorable overall survival (OS) and a decreased risk of non-relapse mortality (NRM) (HR of OS 0.603 [95% CI: 0.400–0.909], P = 0.016; HR of NRM 0.506 [95% CI: 0.300–0.856], P = 0.011). The use of ATG in female-to-male allo-HCT resulted in survival outcomes that were almost equivalent to those in the male-to-male allo-HCT group. Therefore, GVHD prophylaxis with ATG might overcome the inferiority of survival outcomes in female-to-male allo-HCT.

DOI： 10.1038/s41598-023-34442-y

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その他リンク： https://www.nature.com/articles/s41598-023-34442-y

掲載種別：研究論文（学術雑誌）   出版者・発行元：American Society for Clinical Investigation  

DOI： 10.1172/jci.insight.162180

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: α-mannan from Candida albicans reportedly induces Th17-mediated pulmonary graft-versus-host disease (GVHD) in mouse models. This study aimed to evaluate the association between candidemia and noninfectious interstitial pneumonia (IP) in allogeneic hematopoietic cell transplantation (HCT) recipients. METHODS: Using a Japanese transplant registry database, we analyzed 9143 pediatric and adult patients with hematological malignancies who underwent their first (n = 7531) or second (n = 1612) allogeneic HCT between 2009 and 2019. RESULTS: Noninfectious IP was observed in 694 patients at a median (range) of 63 (0-1292) days after HCT. Candidemia occurred in 358 patients at a median (range) of 31 (0-903) days after HCT. Candidemia treated as a time-dependent covariate was significantly associated with an increased incidence of noninfectious IP (hazard ratio [HR], 2.51; 95% CI, 1.48-4.25), along with total body irradiation (>8 Gy; HR, 1.57; 95% CI, 1.18-2.10) and malignant lymphoma (vs acute myeloid leukemia; HR, 1.30; 95% CI, 1.004-1.69). On the other hand, prompt platelet recovery (HR, 0.58; 95% CI, 0.45-0.75) and acute lymphoblastic leukemia (vs acute myeloid leukemia; HR, 0.68; 95% CI, 0.49-0.94) were associated with reduced incidence of noninfectious IP. The median survival after the development of noninfectious IP in patients with prior candidemia was significantly shorter than that in those without it (22 days vs 59 days; P < .001). CONCLUSIONS: Candidemia was associated with an increased incidence of noninfectious IP. The prognosis of noninfectious IP after candidemia was extremely poor.

DOI： 10.1093/ofid/ofad163

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記述言語：日本語   出版者・発行元：(一社)日本輸血・細胞治療学会  

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記述言語：日本語   出版者・発行元：(株)ニュー・サイエンス社  

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記述言語：日本語   出版者・発行元：(一社)日本輸血・細胞治療学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Mechanisms of prolonged cytopenia (PC) after chimeric antigen receptor (CAR) T-cell therapy, an emerging therapy for relapsed or refractory diffuse large B-cell lymphoma, remain elusive. Haematopoiesis is tightly regulated by the bone marrow (BM) microenvironment, called the 'niche'. To investigate whether alterations in the BM niche cells are associated with PC, we analysed CD271+ stromal cells in BM biopsy specimens and the cytokine profiles of the BM and serum obtained before and on day 28 after CAR T-cell infusion. Imaging analyses of the BM biopsy specimens revealed that CD271+ niche cells were severely impaired after CAR T-cell infusion in patients with PC. Cytokine analyses after CAR T-cell infusion showed that CXC chemokine ligand 12 and stem cell factor, niche factors essential for haematopoietic recovery, were significantly decreased in the BM of patients with PC, suggesting reduced niche cell function. The levels of inflammation-related cytokines on day 28 after CAR T-cell infusion were consistently high in the BM of patients with PC. Thus, we demonstrate for the first time that BM niche disruption and sustained elevation of inflammation-related cytokines in the BM following CAR T-cell infusion are associated with subsequent PC.

DOI： 10.1111/bjh.18747

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記述言語：英語  

DOI： 10.1002/ajh.26839

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

The unbalanced translocation der (1;7)(q10;p10) is a characteristic cytogenetic abnormality observed in myelodysplastic syndrome (MDS). A 63-year-old man presented to our hospital with fever and lung disease. The chromosomal analysis of bone marrow cells showed 46, XY, +1, der (1;7)(q10;p10) in all four metaphases. The patient was diagnosed with MDS. Bronchoscope examination revealed organizing pneumonia. The patient's eosinophil count rose to 39% after 30 days. His fever and dyspnea worsened, and a skin rash (systemic erythema) appeared simultaneously. Therefore, the patient was commenced on azacitidine and corticosteroids. Although treatment with both drugs could control disease progression transiently, the WT-1 value and the percentage of myeloblasts in the patient's bone marrow increased. Therefore, the patient received hematopoietic stem cell transplantation from his haplo-identical donor daughter. Some reports have demonstrated that patients with MDS with der (1;7)(q10;p10) have better prognosis than those with other abnormalities, such as -7/7q-. However, reported cases with severe complications show very poor prognosis. MDS with der (1;7)(q10;p10) complicated by eosinophilia and organizing pneumonia have not been reported, and its prognosis is expected to be very poor. Our case suggests that such cases might quickly require hematopoietic stem cell transplantation before the disease worsens.

DOI： 10.11406/rinketsu.64.619

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掲載種別：研究論文（学術雑誌）   出版者・発行元：The Japan Society for Hematopoietic Stem Cell Transplantation  

DOI： 10.7889/tct-23-014

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1182/bloodadvances.2022008991

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Non-infectious pulmonary complications (NIPCs) after allogeneic hematopoietic stem cell transplantation (HSCT) are associated with poor outcomes. It is important to maximize the effectiveness of primary treatment because secondary treatment has not been established. We analyzed data from 393 patients who underwent allogeneic HSCT during a 10-year period. Thirty-seven were diagnosed with NIPCs, which consisted of idiopathic pneumonia syndrome, bronchiolitis obliterans, and interstitial lung disease including cryptogenic organizing pneumonia. Among these, 18 died (Dead group) while 19 remained alive (Alive group) during the study period. The median time between NIPC diagnosis and first administration of ≥ 1 mg/kg/day corticosteroids (prednisolone dose equivalent) was significantly longer in the Dead group than the Alive group, at 9 days versus 4 days (p = 0.01). We further divided these cases into those who received prednisolone within seven days and after 8 days. We found that the ≤ 7 days group were more likely to survive after their NIPC diagnosis compared to the ≥ 8 days group (p = 0.06). Our analysis showed that early initiation of corticosteroid therapy is associated with long-term survival in NIPCs.

DOI： 10.1007/s12185-022-03517-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Reduced-intensity conditioning (RIC) regimens have long-term outcomes that are generally comparable to those with myeloablative conditioning (MAC) due to a lower risk of NRM but a higher risk of relapse. However, it is unclear how we should select the conditioning intensity in individual cases. We propose the Risk assessment for the Intensity of Conditioning regimen in Elderly patients (RICE) score. We retrospectively analyzed 6147 recipients aged 50-69 years using a Japanese registry database. Based on the interaction analyses, advanced age (≥ 60 y), Hematopoietic Cell Transplantation-Specific Comorbidity Index (≥ 2), and umbilical cord blood were used to design a scoring system to predict the difference in an individual patient's risk of nonrelapse mortality (NRM) between MAC and RIC - the RICE score, which is the sum of these three factors: 0 or 1, low RICE score; or 2 or 3, high RICE score. In multivariate analyses, RIC was significantly associated with a decreased risk of NRM in patients with a high RICE score (training cohort: HR, 0.73, 95%CI, 0.60-0.90, P = 0.003; validation cohort: HR, 0.57, 95%CI, 0.43-0.77, P < 0.001). In contrast, we found no significant differences in NRM between MAC and RIC in patients with a low RICE score (training cohort: HR, 0.99, 95%CI, 0.85-1.15, P = 0.860; validation cohort: HR, 0.81, 95%CI, 0.66-1.01, P = 0.061). In summary, a new and simple scoring system, the RICE score, appears to be useful for personalizing the conditioning intensity and might improve transplant outcomes in elderly patients.

DOI： 10.1182/bloodadvances.2022008706

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The incidence of severe adverse events (SAEs) and associated risk factors in hematopoietic cell transplantation donors needs to be clarified for related donors (relatives of the transplant recipient), whose criteria for donation are more lenient than for unrelated donors. Data from related donors registered in the Japanese national data registry database between 2005 and 2021 were evaluated to determine the association of short-term SAE incidence with donor characteristics at registration.Fourteen of 4339 bone marrow (BM) donors (0.32%) and 54 of 10,684 peripheral blood stem cell (PBSC) donors (0.51%) experienced confirmed SAEs during the short donation period. No deaths were observed. Past medical history was a common risk factor for SAEs in both BM and PBSC donors. Age of 60 years or older and female sex were identified as risk factors for SAEs in PBSC donors. Female sex was also a risk factor for poor mobilization, which resulted in discontinuation of PBSC collection.Although donors should be selected carefully, a certain level of safety is ensured for related donors in Japan. Donor safety should be further increased by improving the selection method for related donors and extending the follow-up period.

DOI： 10.1007/s12185-022-03489-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Fatal cardiac complications can occur from the early to late phases after hematopoietic cell transplantation (HCT). Herein, the Japanese transplant registry database was used to retrospectively analyze health records of 33,791 allogeneic HCT recipients to elucidate the pathogenesis and risk factors involved. Overall, 527 patients died of cardiac complications at a median of 130 (range 0-3924) days after HCT. The cumulative incidence of fatal cardiac complications was 1.2% (95% confidence interval [CI]: 1.0-1.3) and 1.6% (95% CI: 1.5-1.8) at 1 and 5 years after HCT, respectively. Fatal cardiovascular events were significantly associated with an HCT-specific comorbidity index (HCT-CI) score of ≥1 specific to the three cardiovascular items, lower performance status, conditioning regimen cyclophosphamide dose of >120 mg/kg, and female sex. Cardiovascular death risk within 60 days after HCT was associated with the type of conditioning regimen, presence of bacterial or fungal infections at HCT, and number of blood transfusions. Contrastingly, late cardiovascular death beyond 1 year after HCT was associated with female sex and older age. Lower performance status and positive cardiovascular disease-related HCT-CI were risk factors for cardiac complications in all phases after HCT. Systematic follow-up may be necessary according to the patients' risk factors and conditions.

DOI： 10.1002/hon.3101

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A conditioning regimen is an essential prerequisite of allogeneic hematopoietic stem cell transplantation for patients with myelodysplastic syndrome (MDS). However, the optimal conditioning intensity for a patient may be difficult to establish. This study aimed to identify optimal conditioning intensity (reduced-intensity conditioning regimen [RIC] or myeloablative conditioning regimen [MAC]) for patients with MDS. Overall, 2567 patients with MDS who received their first HCT between 2009 and 2019 were retrospectively analyzed. They were divided into a training cohort and a validation cohort. Using a machine learning-based model, we developed a benefit score for RIC in the training cohort. The validation cohort was divided into a high-score and a low-score group, based on the median benefit score. The endpoint was progression-free survival (PFS). The benefit score for RIC was developed from nine baseline variables in the training cohort. In the validation cohort, the hazard ratios of the PFS in the RIC group compared to the MAC group were 0.65 (95% confidence interval [CI]: 0.48-0.90, P = 0.009) in the high-score group and 1.36 (95% CI: 1.06-1.75, P = 0.017) in the low-score group (P for interaction < 0.001). Machine-learning-based scoring can be useful for the identification of optimal conditioning regimens for patients with MDS.

DOI： 10.1038/s41409-022-01871-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0273749

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.jcyt.2022.05.009

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記述言語：英語   出版者・発行元：(一社)日本血液学会  

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記述言語：英語  

DOI： 10.1111/tme.12916

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: For pediatric recipients, red blood cells (RBCs) are added to bone marrow (BM) collections before low RBC volume BM processing using COBE Spectra (COBE) or Spectra Optia (Optia). However, the processing efficiency of this approach has not been evaluated. This study aimed to evaluate RBC depletion and nucleated cell subpopulation recovery rates in third-party RBC-manipulated BM products processed with the COBE or Optia. STUDY DESIGN AND METHODS: We retrospectively collected data on RBC depletion from low RBC volume BM with third-party RBCs (manipulated group) and on conventional large-volume, BM (unmanipulated group) processing performed between September 2010 and December 2021. All procedures were performed using COBE or Optia. RESULTS: The median residual RBC volume in the manipulated group was 9.5 ml in COBE and 2.5 ml in Optia (p = .01). The median total nucleated cell (TNC) and mononuclear cell (MNC) were comparable between the manipulated groups using each cell separator (TNC, 40.8 vs. 47.1%; MNC, 78.3 vs. 79.4%). The manipulation did not adversely affect TNC and MNC recoveries in either device. In addition, Optia achieved similar CD34+ cell recovery to that in large-BM-volume processing using the same device (147.5 vs. 184.5%, p = .112). During a follow-up period, neutrophil engraftment was achieved in all patients who received third-party RBC-manipulated grafts, and platelet engraftment was achieved in all cases, except one. CONCLUSION: The addition of third-party RBC to low RBC volume BM collections from or for pediatric patients does not have any negative impact on either RBC depletion or hematopoietic cell recovery during processing with the widely used cell separator.

DOI： 10.1111/trf.17039

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The effects of allogeneic hematopoietic stem cell transplantation (allo-HSCT) on systemic chronic active Epstein-Barr virus infection (sCAEBV) are yet to be analyzed in a large number of patients. Using the Japanese registry database, Transplant Registry Unification Management Program, we investigated the outcomes of 102 sCAEBV patients who underwent allo-HSCT. The median age at HSCT was 21 years, and the three-year overall survival (3-year OS) rate was 72.5%. Of the 90 patients whose viral load after allo-HSCT was evaluated, 56 (62.2%) achieved a virological complete response, defined by the complete resolution of disease activity with a significant decrease in EBV-DNA in peripheral blood. The multivariate Cox proportional hazard model indicated that advanced age, in adolescents and young adults (AYA) (age, 15-39) and adults (age, ≥40 years) was a risk factor of poor OS. The hazard ratios (HRs) of the AYA and adult groups were 10.87 (95% confidence interval [CI]: 1.98-59.56, p = .006) and 15.93 (95% CI: 2.45-103.8, p = .004), respectively. Disease activity (HR 5.74), elevated soluble IL-2 receptor (sIL-2R) (≥ median, 691 U/mL) at HSCT (HR 6.93), and conditioning without radiotherapy (HR 3.53) were also independently associated with poor survival. Notably, 79% of radiotherapy doses were less than 6 Gy. Regardless of the presence of hemophagocytic lymphohistiocytosis, the group with a high sIL-2R level (≥2000 U/mL) showed a poorer prognosis. Although allo-HSCT is the only curative therapy for sCAEBV, treatment strategies need to be improved for high-risk patients, especially those with high levels of sIL-2R.

DOI： 10.1002/ajh.26544

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記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

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記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Vaccine-preventable disease (VPD) infections are more severe in immunocompromised hosts. Vaccination against measles, mumps, rubella, and varicella zoster (VZV) (MMRV) is therefore recommended for hematopoietic stem cell transplantation (HCT) recipients. However, studies on adult HCT recipients with VPD infections are limited. At our institution, we have systematically conducted serological MMRV tests as a part of check-up examinations during long-term follow-up (LTFU) after HCT since 2015. This retrospective study aimed to evaluate changes in the serostatus between before and 2 years after allogeneic HCT. Among 161 patients, the pre-transplant seropositivity was 82.7% for measles, 86.8% for mumps, 84.2% for rubella, and 94.3% for VZV. Among 56 patients who underwent LTFU including serological MMRV tests at 2 years after HCT, the percentages maintaining seroprotective antibody levels for measles, mumps, rubella and VZV were 71.5% (40/56), 51.8% (29/56), 48.2% (27/56), and 60.7% (34/56), respectively. Vaccination was recommended for 22 patients, and 12 were vaccinated. Among the 12 vaccinated patients, rates of seroconversion were examined in 2-6 patients for each of the four viruses. They were 100% (3/3) for measles, 33.3% (1/3) for mumps, 50% (3/6) for rubella, and 0% (0/2) for VZV. Further studies are warranted to clarify the effect of vaccination in adult HCT recipients.

DOI： 10.18926/AMO/63718

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: CD34+ cell collection efficiency (CE) is the determining factor when calculating processed blood volume (PBV) for leukapheresis (LP). However, the factors affecting CE in the continuous mononuclear cell collection (cMNC) protocol performed by the Spectra Optia apheresis system are not well established. STUDY DESIGN AND METHODS: We retrospectively collected the data from 147 consecutive apheresis procedures across 106 healthy donors and 27 patients completed between July 2016 and December 2020 at the Okayama University Hospital. All procedures were performed using the Optia cMNC protocol. RESULTS: The median CD34+ CE2 was significantly higher in the donor samples (64.3%) than in the patient samples (46.8%) (p < .0001). WBC counts, hematocrit, and platelet counts were all significantly higher in the donors than in the patients, and there was a moderate positive correlation between CD34+ CE2 and hematocrit (r = .47, p < .0001), with the equation of the line being y = 1.23x + 12.23. In contrast, there was only a very weak correlation between CD34+ CE2 and WBC or platelet count. In addition, low hematocrit correlated with an increased time to interface formation. CONCLUSION: These data revealed the negative impact of low hematocrit on the efficiency of CD34+ cell collection when using the Optia cMNC protocol and suggest that hematocrit values should also be considered when determining PBV.

DOI： 10.1111/trf.16856

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.transci.2022.103453

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Therapy-related myelodysplastic syndromes (t-MDS) are generally progressive and associated with poorer outcomes than de novo MDS (d-MDS). To evaluate the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for t-MDS, we conducted a propensity score matched-pair analysis of patients with t-MDS and d-MDS using a nationwide database. A total of 178 patients with t-MDS underwent allo-HSCT between 2001 and 2018, and 178 out of 3123 patients with d-MDS were selected. The probability of 3-year overall survival rate was 40.0% and 50.0% in the t-MDS and d-MDS groups, respectively (p = 0.032). The 3-year transplant-related mortality was 30.9% and 19.0% in the t-MDS and d-MDS groups, respectively (p = 0.005). The 3-year cumulative incidence of relapse was 32.8% and 33.0% in the t-MDS and d-MDS groups, respectively (p = 0.983). A multivariate analysis identified four adverse factors for overall survival in the t-MDS group: age ≥ 55 years (hazard ratio [HR], 2.09; 95% CI, 1.11-3.94; p = 0.023), the poor cytogenetic risk group (HR, 2.19; 95% CI, 1.40-4.19; p = 0.019), performance status at allo-HSCT 2-4 (HR, 2.14; 95% CI, 1.19-3.86; p = 0.011), and a shorter interval from diagnosis to transplantation (<8 months; HR, 1.61; 95% CI, 1.00-2.57; p = 0.048). The most frequent cause of transplant-related death was the infectious complications (21.6%) in t-MDS group and organ failure (12.5%) in d-MDS group. In conclusion, allo-HSCT potentially provides long-term remission in patients with t-MDS; however, further efforts to reduce transplant-related death are needed.

DOI： 10.1002/hon.2991

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

There are limited data comparing myeloablative conditioning with fludarabine/busulfan (Flu/Bu4) and reduced-intensity conditioning with fludarabine/busulfan (Flu/Bu2) in patients with myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). We retrospectively analyzed nationwide registry data and compared the outcomes of adult patients with MDS receiving Flu/Bu4 and Flu/Bu2 by propensity score (PS) matching. Patients who met the following criteria were eligible for enrollment: (1) age ≥16 years; (2) diagnosis of de novo MDS; (3) first allo-HSCT between 2006 and 2018; (4) related bone marrow transplantation (BMT) or peripheral blood stem cell transplantation from an HLA-matched donor, unrelated BMT from an HLA-matched or HLA-1 allele-mismatched donor, or unrelated cord blood transplantation; and (5) receiving Flu/Bu4 or Flu/Bu2 as a conditioning regimen. Flu/Bu4 comprised intravenous busulfan (total dose, 12.8 mg/kg) combined with fludarabine (total dose, 125-180 mg/m2). Flu/Bu2 comprised intravenous busulfan (total dose, 6.4 mg/kg) combined with the same dose of fludarabine. To minimize selection bias and confounding factors, we performed a propensity score (PS)-matched analysis. The primary endpoint was overall survival (OS) after allo-HSCT. A total of 3386 patients with de novo MDS underwent their first allo-HSCT between 2006 and 2018. Among them, 202 patients were assigned each to the Flu/Bu4 and Flu/Bu2 groups after PS-matched analysis. The median age was 61 (interquartile, 57-65) years. The 3-year OS rates were 44.8% (95% confidence interval [CI], 37.1-52.1%) and 46.9% (95% CI, 39.2-54.2%) in the Flu/Bu4 and Flu/Bu2 groups, respectively (P = .67). The 3-year rates of graft-versus-host disease (GVHD)-free survival, relapse-free survival (GRFS) were 28.8% (95% CI, 22.2-35.7%) and 33.0% (95% CI, 26.2-40.0%), respectively (P = .36). The 3-year cumulative incidence rates of relapse were 28.9% (95% CI, 22.6-35.6%) and 30.0% (95% CI, 23.6-36.6%), respectively (P = .47). The 3-year cumulative incidence rates of non-relapse mortality (NRM) were 28.2% (95% CI, 21.7-35.0%) and 27.1% (95% CI, 20.6-33.9%), respectively (P = .60). The 100-day cumulative incidence rate of grade II-IV acute GVHD was significantly higher in the Flu/Bu4 group than in the Flu/Bu2 group (41.7% [95% CI, 34.8%-48.4%] versus 29.3% [95% CI, 23.2%-35.7%], P = 0.012). To identify patients who had more favorable outcomes with 1 of the 2 regimens, we compared the outcomes between the 2 groups after stratifying by age, hematopoietic cell transplantation-comorbidity index, cytogenetic risk, disease status at allo-HSCT, stem cell source, and donor type. OS, GRFS, relapse, and NRM did not differ between the 2 groups in any subgroup analyses. There were no significant interactions between the choice of conditioning regimens and any other factors. There are no differences in survival between Flu/Bu4 and Flu/Bu2, although our study population was highly selected by PS matching. Data from more patients and prospective studies are needed to determine the optimal intensity of conditioning regimens in patients with MDS.

DOI： 10.1016/j.jtct.2022.03.011

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The disease-specific impact of anti-thymocyte globulin (ATG) in allogeneic hematopoietic cell transplantation (allo-HCT) has not been determined. We retrospectively assessed the impact of ATG in allo-HCT using nationwide registry data from the Japan Society for Transplantation and Cellular Therapy. We included patients who received their first allo-HCT between 2007 and 2018 for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or malignant lymphoma (ML). In total, 8747 patients were included: 7635 patients did not receive ATG and 1112 patients received ATG as GVHD prophylaxis. The median follow-up period of surviving patients was 1457 days. There was no significant impact of pretransplant ATG on the OS or NRM rates in patients with ALL, AML, or ML. In patients with MDS, the probability of 3-year OS was 53.3% in the non-ATG group and 64.2% in the ATG group (P = 0.001). The cumulative incidence rates of relapse and NRM at 3 years were 14.2% and 30.3% (95% CI 27.2-33.3%), respectively, in the non-ATG group and 17.1% and 18.1% in the ATG group (P = 0.15 and P < 0.001). The same finding was observed in a propensity-score matched cohort. Our study suggests that the clinical benefit of ATG could vary among hematological diseases.

DOI： 10.1038/s41409-022-01569-x

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1007/s12185-022-03306-y

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その他リンク： https://link.springer.com/article/10.1007/s12185-022-03306-y/fulltext.html

掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1007/s12185-022-03290-3

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その他リンク： https://link.springer.com/article/10.1007/s12185-022-03290-3/fulltext.html

記述言語：英語  

Venetoclax (VEN) is an oral B-cell lymphoma-2 (BCL-2) inhibitor that has been widely used to treat various hematological disorders. Recent studies have demonstrated that VEN in combination with fludarabine-enhanced high-dose cytarabine (FLA) is effective for treating relapsed or refractory acute myeloid leukemia (AML). In the combination therapy, salvage chemotherapy and VEN are basically concurrently administrated; however, further optimization may enable the treatment to apply to larger numbers of patients with various clinical backgrounds. Here, we describe a case of refractory AML treated with a sequential combination of the intensive chemotherapy (fludarabine, cytarabine, and mitoxantrone; FLAM) and VEN/AZA to bridge to an unrelated cord blood transplantation (uCBT). By continuously adding VEN/AZA after FLAM, the patient achieved morphologic leukemia free state with only minor toxicities. Blood cell counts did not recover until the time of transplantation because of the deep myelosuppression caused by the treatment sequence, but the infection risk was safely managed during this period. After engraftment, maintenance therapy with VEN/AZA was performed, and the patient has survived without disease recurrence for over 9 months after transplantation. Our case suggests that bridging therapy with VEN and AZA from the time of the last chemotherapy to allogeneic transplantation may provide an effective and tolerable treatment strategy for refractory AML. Further studies of larger numbers of cases are needed to validate the effectiveness of this treatment.

DOI： 10.1159/000526697

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Myeloablative conditioning with fludarabine/busulfan (Flu/Bu4) prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) is effective for acute myeloid leukemia. However, the effectiveness of Flu/Bu4 for myelodysplastic syndrome (MDS) remains poorly understood. Therefore, we retrospectively analyzed nationwide registry data in Japan from 2006 to 2018 and compared transplant outcomes of adult MDS patients receiving Flu/Bu4 and busulfan/cyclophosphamide (Bu4/Cy) using propensity score (PS) matching. The primary endpoint was overall survival (OS). Among 2,482 MDS patients, 153 patients were assigned each to the Flu/Bu4 and Bu4/Cy groups. The 3-year OS rates were 52.7% (95% confidence interval [CI], 43.8-60.8%) and 49.5% (95% CI, 40.8-57.6%) in the Flu/Bu4 and Bu4/Cy group, respectively (P = 0.548). The 3-year progression-free survival (P = 0.858), the cumulative incidence of relapse (P = 0.536), and cumulative incidence of non-relapse mortality (P = 0.684) were not significantly different between the two groups. According to the findings of subgroup analyses, no patient had a favorable OS when using either of the two regimens. In conclusion, although our PS-matched cohort mainly comprised older patients who had a low hematopoietic cell transplantation-comorbidity index and low-risk disease status, Flu/Bu4 could be an alternative to Bu4/Cy for MDS patients prior to allo-HSCT.

DOI： 10.1038/s41409-021-01447-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

To evaluate whether outcomes following allogeneic hematopoietic cell transplantation differ according to disease type, a three-way comparison for patients with de novo acute myeloid leukemia (AML) (n = 3318), AML evolving from myelodysplastic syndromes (MDS) (n = 208), and MDS with excess blasts (MDS-EB) (n = 994) was performed. The 5-year probabilities of overall survival (OS) for de novo AML, AML evolving from MDS, and MDS-EB were 60%, 42%, and 41% (p < 0.001), respectively. Multivariate analysis revealed that, compared to de novo AML, AML evolving from MDS was associated with a higher risk of NRM (p = 0.030) and MDS-EB with a higher risk of relapse (p < 0.001), both leading to lower OS (p = 0.010 and p < 0.001, respectively). These findings demonstrate inter-disease differences in post-transplant outcomes and highlight the needs to reduce NRM for AML evolving from MDS and to reduce relapse for MDS-EB.

DOI： 10.1080/10428194.2021.1961242

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Marginal zone lymphoma (MZL) arising from the anterior mediastinum is rare. In the majority of reported cases, the tumor was incidentally discovered, reflecting its indolent clinical features. We present a 38-year-old woman who had no medical history, and presented with a bulky anterior mediastinal tumor complicated by life-threatening compression of the vasculature and bronchi. Biopsy specimens of the neoplasm suggested transformed diffuse large B-cell lymphoma (DLBCL) from MZL. To our best knowledge, this is the first case report of anterior mediastinum MZL associated with an aggressive clinical course and life-threatening complications likely due to transformation to DLBCL.

DOI： 10.3960/jslrt.21010

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We retrospectively compared the outcomes of reduced-intensity conditioning (RIC) transplantation from matched related donors (MRD; n = 266), matched unrelated donors (MUD; n = 277), and umbilical cord blood (UCB; n = 513) for mature lymphoid malignancies. The 3-year overall survival rates for the MRD, MUD, and UCB groups were 54%, 59%, and 40%, respectively (P < 0.001). Multivariate analysis showed no differences in survival between the MRD group and the MUD or UCB group. However, survival was significantly affected by the conditioning regimen and graft-versus-host disease (GVHD) prophylaxis in the UCB group, but not in the MRD and MUD groups. Notably, multivariate analysis showed that the risk of overall mortality in the UCB recipients who received the optimal conditioning regimen and GVHD prophylaxis (n = 116) was lower than that in the MRD group (relative risk [RR], 0.69; P = 0.03) and tended to be lower than that in the MUD group (RR, 0.75; P = 0.09). Our results suggest that UCB transplantation performed with the optimal conditioning regimen and GVHD prophylaxis is highly effective. Moreover, UCB is readily available. Thus, UCB transplantation with the optimal conditioning regimen and GVHD prophylaxis is preferable to MUD transplantation when MRD are not available in the setting of RIC transplantation for mature lymphoid malignancies.

DOI： 10.1038/s41409-021-01525-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A pre-emptive strategy has successfully decreased cytomegalovirus (CMV) disease after allogeneic hematopoietic cell transplantation (HCT). However, some recipients still develop CMV gastroenteritis, especially after acute graft-versus-host disease (aGVHD), and its incidence, risk factors, and prognostic impact remain to be elucidated. We retrospectively analyzed 3759 consecutive adult patients who developed grade II-IV aGVHD using a Japanese registry database. The cumulative incidence of CMV gastroenteritis was 5.7% by day 365 from the development of grade II-IV aGVHD. Advanced age (hazard ratio [HR], 1.60; 95% confidence interval [CI], 1.16-2.22; P = 0.004), GVHD prophylaxis with mycophenolate mofetil and calcineurin inhibitor (HR, 1.73; 95% CI, 1.08-2.77; P = 0.024), lower-gut aGVHD (HR, 2.17; 95% CI, 1.58-2.98; P < 0.001), and the use of systemic steroids (HR, 1.78; 95% CI, 1.16-2.74; P = 0.008) were independent risk factors for CMV gastroenteritis. Development of CMV gastroenteritis was associated with an increased risk of nonrelapse mortality (HR, 1.89; 95% CI, 1.50-2.39; P < 0.001). Moreover, letermovir prophylaxis significantly reduced both the incidence of CMV gastroenteritis (HR, 0.50; 95% CI, 0.25-0.99; P = 0.047) and the risk of nonrelapse mortality (HR, 0.72; 95% CI, 0.52-0.99; P = 0.043). In summary, CMV gastroenteritis is a life-threatening complication that sets the need for preventive strategies with letermovir and targeted surveillance.

DOI： 10.1182/bloodadvances.2021005885

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2169/internalmedicine.7307-21

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 72-year-old man presented with chorea while undergoing treatment for recurrence of nodal peripheral T-cell lymphoma with T follicular helper (TFH) phenotype. An examination by brain N-isopropyl-p-iodoamphetamine (123I-IMP)-single photon emission computed tomography (SPECT) revealed no abnormalities other than a decreased cerebral blood flow (CBF) in the left striatum. After four courses of salvage chemotherapy, his clinical symptoms and asymmetric cerebral perfusion improved, suggesting that the decreased CBF had caused chorea. The significance of brain SPECT has not been fully clarified in patients with chorea-associated malignant lymphoma, warranting further investigations. Brain SPECT is an alternative approach to identify abnormalities in such patients.

DOI： 10.2169/internalmedicine.7180-21

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIM: Chronic graft-versus-host disease (cGVHD) is a major cause of nonrelapse morbidity and mortality following hematopoietic stem cell transplantation (HSCT). α-Galactosylceramide (α-GC) is a synthetic glycolipid that is recognized by the invariant T-cell receptor of invariant natural killer T (iNKT) cells in a CD1d-restricted manner. Stimulation of iNKT cells by α-GC leads to the production of not only immune-stimulatory cytokines but also immune-regulatory cytokines followed by regulatory T-cell (Treg) expansion in vivo. METHODS: We investigated the effect of iNKT stimulation by liposomal α-GC just after transplant on the subsequent immune reconstitution and the development of sclerodermatous cGVHD. RESULTS: Our study showed that multiple administrations of liposomal α-GC modulated both host- and donor-derived iNKT cell homeostasis and induced an early expansion of donor Tregs. We also demonstrated that the immune modulation of the acute phase was followed by the decreased levels of CXCL13 in plasma and follicular helper T cells in lymph nodes, which inhibited germinal center formation, resulting in the efficient prevention of sclerodermatous cGVHD. CONCLUSIONS: These data demonstrated an important coordination of T- and B-cell immunity in the pathogenesis of cGVHD and may provide a novel clinical strategy for the induction of immune tolerance after allogeneic HSCT.

DOI： 10.1002/iid3.425

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Antithymocyte globulin (ATG) has been shown to reduce chronic graft-versus-host disease (GVHD) particularly in allogeneic peripheral blood stem cell transplantation (PBSCT) from unrelated donors; however, anti-GVHD effects of lower doses of ATG remains to be elucidated. We conducted a nationwide retrospective study to compare the outcomes of unrelated PBSCT with or without rabbit ATG (thymoglobulin) in 287 patients. A median ATG dose was 2.0 mg/kg. The primary endpoint, the cumulative incidence of moderate-severe chronic GVHD at 2 years was 22.1% in the ATG group, which was significantly less than that in the non-ATG group (36.3%, P = 0.025). The ATG group had a higher incidence of immunosuppressant discontinuation, GVHD-free, relapse-free survival, and moderate-severe chronic GVHD-free, relapse-free survival at 2 years compared to the non-ATG group. The incidences of grade III-IV aGVHD and moderate-severe chronic GVHD were significantly higher in patients with high absolute lymphocyte count (ALC) before the administration of ATG, whereas relapse rate was significantly higher in patients with low ALC before ATG. In conclusion, low-dose ATG effectively suppresses chronic GVHD in unrelated PBSCT, and ALC before ATG may be a potential predictor for GVHD and relapse.

DOI： 10.1038/s41409-021-01314-w

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare indolent B-cell neoplasm, and a gain-of-function mutation in the myeloid differentiation primary response 88 (MYD88), L265P, is a commonly recurring mutation in patients with WM/LPL. Histological transformation of WM/LPL to an aggressive lymphoma such as diffuse large B-cell lymphoma (DLBCL) is rare, and transformed DLBCL has a worse prognosis than de novo DLBCL, partly because transformed DLBCL is mostly classified as non-germinal center B-cell-like (non-GCB) subtype. We herein describe a 75-year-old man with DLBCL with a history of WM/LPL. DLBCL in this patient showed the GCB subtype, and the light chain restriction of DLBCL was different from that of the antecedent WM/LPL, indicating that the two types of lymphoma cells had distinctive origins. However, DLBCL in this patient harbored the MYD88 L265P mutation, and polymerase chain reaction and Sanger sequencing of the DLBCL and WM/LPL for immunoglobulin heavy chain gene rearrangement suggested a clonal relationship between the two lymphomas. Since the outcome of transformed DLBCL is worse than for de novo DLBCL, it is important to evaluate the clonal relationship between primary WM/LPL and the corresponding transformed DLBCL, even if the DLBCL expresses a GCB subtype or discordant light chain restriction.

DOI： 10.1007/s12185-021-03157-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although graft failure (GF) is a fatal complication after allogeneic stem cell transplantation (SCT), no mortality risk assessments after salvage SCT have been reported. We developed a comprehensive prognostic scoring system consisting of patient and comorbidity factors with 470 patients as a training cohort out of 940; these patients underwent salvage SCT for GF. The multivariate analysis demonstrated that older age, poorer performance status, a continuation of antimicrobial treatment, and severe organ dysfunction were independently associated with worse overall survival (OS) and non-relapse mortality (NRM). Based on each factor's hazard ratio, weighted scores of 1-3 were assigned to these factors. Using the summed scores (0-8), a prognostic scoring system successfully stratified outcomes after salvage SCT in the cohort. For patients in the low (0-2, n = 122), intermediate (3-4, n = 209), and high score (5-8, n = 110) groups, the 1-year OS was 62.8%, 40.8%, and 14.2%, respectively (P < 0.001), whereas the 1-year NRM was 24.1%, 43.9%, and 72.7%, respectively (P < 0.001). The prognostic value of the scoring system was confirmed in the validation cohort (n = 470). Our scoring system is useful for predicting survival after salvage SCT.

DOI： 10.1038/s41409-021-01310-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Despite a strong association between acute graft-versus-host disease (GVHD) and cytomegalovirus reactivation (CMVR), the joint effect of acute GVHD and CMVR on nonrelapse mortality (NRM) has not been well studied. METHODS: We evaluated the impact of CMVR on NRM stratified according to the development of acute GVHD using a landmark method. This study included 6078 patients who received their first allogeneic hematopoietic cell transplantation (HCT) with a preemptive strategy for CMVR between 2008 and 2017. RESULTS: The cumulative incidences of grade 2-4 acute GVHD (G24GVHD), CMVR by day 100, and CMV disease by day 365 were 37.3%, 52.1%, and 2.9%, respectively. Patients with G24GVHD were associated with the subsequent development of CMVR, and the presence of CMVR also increased the risk of G24GVHD. In a landmark analysis at day 65, the cumulative incidence of NRM at 1 year was 5.4%, 10.0%, 13.9%, and 19.7% in patients with G24GVHD-/CMVR-, G24GVHD-/CMVR+, G24GVHD+/CMVR-, and G24GVHD+/CMVR+, respectively. In a multivariate analysis, CMVR was respectively associated with an increased risk of NRM by day 365 in patients without G24GVHD (hazard ratio [HR], 1.59; 95% confidence interval [CI], 1.24-2.05; P < .001) and with G24GVHD (HR, 1.34; 95% CI, 1.06-1.70; P = .014), but the interaction between G24GVHD and CMVR was not significant (P = .326). Subgroup analyses suggested that the joint effect of acute GVHD and CMVR might vary according to the baseline characteristics. CONCLUSIONS: These data regarding the close relationship between acute GVHD and CMVR should provide important implications for the treatment strategy after HCT.

DOI： 10.1093/cid/ciaa1871

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Posttransplantation cyclophosphamide (PTCy) has become a popular option for haploidentical hematopoietic stem cell transplantation (HSCT). However, personalized methods to adjust immune intensity after PTCy for each patient's condition have not been well studied. Here, we investigated the effects of reducing the dose of PTCy followed by α-galactosylceramide (α-GC), a ligand of iNKT cells, on the reciprocal balance between graft-versus-host disease (GVHD) and the graft-versus-leukemia (GVL) effect. In a murine haploidentical HSCT model, insufficient GVHD prevention after reduced-dose PTCy was efficiently compensated for by multiple administrations of α-GC. The ligand treatment maintained the enhanced GVL effect after reduced-dose PTCy. Phenotypic analyses revealed that donor-derived B cells presented the ligand and induced preferential skewing to the NKT2 phenotype rather than the NKT1 phenotype, which was followed by the early recovery of all T cell subsets, especially CD4+Foxp3+ regulatory T cells. These studies indicate that α-GC administration soon after reduced-dose PTCy restores GVHD-preventing activity and maintains the GVL effect, which is enhanced by reducing the dose of PTCy. Our results provide important information for the development of a novel strategy to optimize PTCy-based transplantation, particularly in patients with a potential relapse risk.

DOI： 10.1038/s41598-021-92526-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Graft-versus-host disease (GVHD) remains to be a significant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). IL-2-inducible T cell kinase (ITK), a TEC cytoplasmic tyrosine kinase, has an essential role in T cell development and receptor signaling. The ITK/Bruton tyrosine kinase inhibitor ibrutinib has been shown to improve chronic GVHD symptoms; however, the effect of ITK selective inhibition on acute GVHD remains unclear. In this study, we evaluated the pharmacological effects of an ITK selective inhibitor (ITKsi) on acute GVHD using murine bone marrow transplantation models. First, we found that CD4+ T cell differentiation toward Th1, Th2, or Th17 was inhibited following ITKsi treatment in a dose-dependent manner while maintaining regulatory T cells in the presence of alloantigens both in vitro and in vivo. ITKsi preferentially inhibited inflammatory cytokine production and in vivo proliferation of alloreactive T cells. We then demonstrated that short-term exposure of donor graft cells to ITKsi significantly delayed the onset of GVHD-associated mortality without compromising the donor cell engraftment and the graft-versus-tumor effect, indicating the potential of ITK selective inhibition in the setting of clinical allogeneic HSCT. These findings suggest that ITK is a potential therapeutic target against GVHD, and the pharmacological ITK inhibitor may serve as a novel strategy for immune regulation after HSCT.

DOI： 10.4049/immunohorizons.2100042

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A bloodstream infection (BSI) is the most common serious infectious complication of hematopoietic stem cell transplantation (HSCT). BSI promotes an inflammatory state, which exacerbates acute graft-versus-host disease (GVHD). We investigated whether a Gram-negative rod bloodstream infection (GNR-BSI), which develops early after allo-HSCT, affected the onset or exacerbated acute GVHD in 465 patients who underwent allo-HSCT from 1995 through 2015 at a single institution. Eighty-eight patients (19%) developed BSI during the study period. Among the cultures, 50 (57%) were Gram-positive cocci (GPC) and 31 (35%) were GNR. Of the 465 patients, 187 (40%) developed acute GVHD of grade II or higher within the first 100 days post-allogeneic HSCT: 124 (27%) had acute GVHD grade II, 47 (10%) had grade III, and 16 (3%) had grade IV. Multivariate analysis revealed that GNR-BSI was a significant risk factor for grade II-IV acute GVHD (grade II-IV: hazard ratio [HR] 1.75, 95% confidence interval [CI] 1.03-2.97; grade III-IV: HR 2.37, 95% CI 1.03-5.43). These results suggest that GNR-BSI may predict the onset and exacerbation of acute GVHD.

DOI： 10.18926/AMO/62219

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記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

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記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Posttransplant relapse represents the greatest obstacle to the success of allogeneic hematopoietic cell transplantation (HCT) for patients with acute myeloid leukemia (AML). This study investigated clinical features and outcomes of posttransplant relapse of AML based on data for 1265 patients with AML suffering relapse after allogeneic HCT conducted during complete remission (CR). Relapse occurred at a median of 6.1 months. The incidence rate of relapse peaked at 29.0 per 100 patient-years during the first 3-6 months period post transplant, after which the rate declined over time, and after 3 years remained consistently at less than 1 per 100 patient-years. The probability of overall survival (OS) after posttransplant relapse was 19% at 2 years, with 68% of deaths being attributed to leukemia. The interval from transplantation to relapse was identified as the strongest indicator for OS. Donor lymphocyte infusion (DLI) and second allogeneic HCT (HCT2) were administered to 152 (12%) and 481 (38%) patients, respectively. Landmark analyses showed some signs of survival benefit when these procedures were performed during CR, but no benefit was gained when performed during non-CR. Our findings clarify clinical features of posttransplant relapse of AML, and indicate the urgent need for developing effective bridging to cellular therapies.

DOI： 10.1038/s41409-020-01163-z

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記述言語：日本語   出版者・発行元：(一社)日本輸血・細胞治療学会  

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記述言語：英語  

Acute promyelocytic leukemia (APL) is a hematological emergency that requires urgent intervention because of the high incidence of early hemorrhagic death. When patients with APL experience a synchronous solid organ tumor, the tumor's treatment must also be done properly. Differentiation-inducing therapy using arsenic trioxide (ATO) has less hematological toxicity compared to cytotoxic chemotherapy and might be preferable for untreated APL patients with a synchronous solid organ tumor. Here we describe the first successful case of untreated APL and synchronous endometrial cancer (in an adult Japanese woman) treated with ATO consolidation therapy and the subsequent surgery and chemotherapy for endometrial cancer.

DOI： 10.18926/AMO/61904

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41409-020-01100-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative post-remission therapy for adult patients with acute myeloid leukemia (AML) in complete remission (CR). The availability of alternative human leukocyte antigen (HLA)-mismatched donors, such as cord blood and haploidentical related donors, could allow patients to receive allogeneic HCT who are without an HLA-matched sibling or unrelated donor. The use of these alternative donors is preferable for patients with advanced disease due to the rapid availability. However, comparative data for cord blood transplantation (CBT) and haploidentical related donor transplantation (haplo-HCT) are limited for adult patients with AML in CR. We sought to compare overall survival (OS); leukemia-free survival (LFS); graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS); and chronic GVHD-free, relapse-free survival (CRFS) between single-unit CBT (SCBT) and haplo-HCT recipients for adult patients with intermediate- or poor-risk AML in CR. We retrospectively analyzed and compared the results of allogeneic hematopoietic cell transplantation in 1313 adult patients with intermediate- or poor-risk AML in CR who received either SCBT (n = 1102) or unmanipulated haplo-HCT (n = 211) between 2007 and 2018 in Japan. Among the whole cohort, the cumulative incidences of neutrophil and platelet recovery were significantly lower in SCBT recipients compared with those in haplo-HCT recipients (P < .001 for neutrophil, P < .001 for platelet). SCBT was significantly associated with a higher incidence of grade II to IV acute GVHD and lower incidence of extensive chronic GVHD compared to haplo-HCT (P = .013 for grades II to IV acute GVHD; P = .006 for extensive chronic GVHD). Haplo-HCT recipients developed a higher incidence of cytomegalovirus (CMV) antigenemia compared to SCBT recipients (P = .004). In the multivariate analysis, there were no significant differences for grades III or IV acute GVHD (hazard ratio [HR], 1.17; 95% confidence interval [CI], .88 to 1.57; P = .26), relapse incidence (HR, 1.09; 95% CI, .76 to 1.58; P = .61), non-relapse mortality (HR, .83; 95% CI, .58 to 1.18; P = .32), OS (HR, .92; 95% CI, .70 to 1.20; P = .56), LFS (HR, .94; 95% CI, .73 to 1.21; P = .67), GRFS (HR, 1.12; 95% CI, .90 to 1.40; P = .27), or CRFS (HR, 1.15; 95% CI, .92 to 1.44; P = .19) between the two donor types. In the propensity score matching analysis, which identified 180 patients in each cohort, there were no significant differences in transplant outcomes between the two donor types, except for delayed neutrophil (P < .001) and platelet recovery (P < .001) and a higher incidence of grades II to IV acute GVHD (P = .052) in SCBT. SCBT and unmanipulated haplo-HCT had similar survival outcomes for adult patients with AML in CR despite the lower hematopoietic recovery and higher grade II to IV acute GVHD in SCBT recipients and the higher CMV antigenemia in haplo-HCT recipients.

DOI： 10.1016/j.jtct.2021.01.023

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記述言語：英語  

DOI： 10.1038/s41598-021-86066-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We evaluated the impact of event-free survival (EFS) status at 24 months (EFS24) and 60 months (EFS60) after hematopoietic stem cell transplantation (HSCT) using registry data. Patients who underwent their first autologous HSCT (auto-HSCT) or allogeneic HSCT (allo-HSCT) for lymphoma between 1981 and 2018 were included. Overall survival was compared with that of the age-, sex, and calendar period-matched general population. A total of 14 977 patients, including 10 964 and 4013 who underwent auto-HSCT and allo-HSCT, respectively, were analyzed. Although patients who achieved EFS24 and EFS60 had favorable outcomes, most had significantly poorer survival rates than the general population. The standardized mortality ratios (SMRs) of patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) were significantly higher than that of the general population even after achieving EFS24 or EFS60. The SMRs of those after auto-HSCT were 2.5 to 3.5 and 2.7 to 3.7, respectively. The SMR was consistently highest in Hodgkin lymphoma (HL) patients after HSCT. By contrast, subsequent survival of patients with primary mediastinal large B-cell lymphoma, intravascular large B-cell lymphoma, or peripheral T-cell lymphoma, not otherwise specified, who achieved EFS60 after auto-HSCT, and those with extranodal natural killer/T-cell lymphoma who achieved EFS60 after allo-HSCT did not significantly differ from that of the general population, with SMRs of 1.6, 1.2, 1.8, and 1.3, respectively. Our results suggest that EFS24 and EFS60 were clinically useful end points after HSCT for lymphoma patients. Furthermore, patients with certain lymphoma subtypes who achieved EFS had a comparable prognosis with that of the general population and were potentially cured after HSCT.

DOI： 10.1182/bloodadvances.2020003735

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記述言語：英語  

DOI： 10.1038/s41375-021-01167-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The safety and efficacy of allogeneic hematopoietic stem cell transplantation (HSCT) for paroxysmal nocturnal hemoglobinuria (PNH) remain unclear. Therefore, we retrospectively analyzed the outcomes of 42 adult patients with PNH who underwent allogeneic HSCT using the registry database of the Japan Society for Hematopoietic Cell Transplantation. The median patient age was 32.5 years. The number of packed red cell (PRC) transfusions was < 20 times in 19 patients and ≥ 20 times in 16; 7 patients had missing data. Stem cell sources were bone marrow (N = 15) or peripheral blood (N = 13) from a related donor or bone marrow (N = 11) and cord blood (N = 3) from an unrelated donor. The cumulative incidence of neutrophil engraftment at day 40 was 81%. Six patients died before engraftment, and the 6-year overall survival (OS) was 74%. The OS of patients with < 20 pretransplant PRC transfusions was significantly higher than that of patients with ≥ 20 pretransplant PRC transfusions (95% vs. 63%; P < 0.05). Moreover, the OS of patients aged < 30 years was significantly higher than that of patients aged ≥ 30 years (90% vs. 59%; P < 0.05). Allogeneic HSCT for PNH could provide favorable survival; however, pretransplant transfusion burden and patient age should be considered when deciding the timing of allogeneic HSCT.

DOI： 10.1007/s12185-020-02982-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The prevention of chronic graft-versus-host disease (cGVHD) is important for recipients of hematopoietic stem-cell transplantation (HSCT). As one of the etiologies, the relationship between early T-cell recovery and subsequent cGVHD development has been the focus of attention. Recently, letermovir (LTV) was approved for preventing cytomegalovirus (CMV) reactivation in the early transplantation phase. Although CMV affects the immune reconstitution after HSCT, the impacts of LTV to prevent CMV reactivation on early T-cell recovery and cGVHD have not been fully investigated. We aimed to identify early T-cell recovery under LTV at day 30 in 15 and 33 recipients from matched related donors (MRDs) and haploidentical donors with post-transplant cyclophosphamide (PTCy-haplo), respectively. Early increases in the levels of total lymphocytes and HLA-DR+ activated T-cells at day 30 were observed under CMV prophylaxis by LTV only in PTCy-haplo recipients and not in MRD recipients. Moreover, PTCy-haplo recipients with LTV showed a significantly higher incidence of cGVHD, but not acute GVHD. Our observations suggest that an early increase in the levels of HLA-DR+ activated T-cells may be implicated in the development of cGVHD in patients treated with PTCy who received LTV. Further studies are warranted to validate our results and elucidate the detailed mechanisms of our new insights.

DOI： 10.3389/fonc.2021.666774

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記述言語：英語  

Owing to the poor prognosis of relapsed or refractory acute lymphoblastic leukemia (ALL), hematopoietic stem cell transplantation (HSCT) followed by effective salvage therapy is required. Inotuzumab ozogamicin (INO) was developed for ALL refractory to standard chemotherapy. However, previous reports suggest that sinusoidal obstruction syndrome (SOS) risk increases in patients with HSCT receiving INO, especially with dual alkylating agents. We report a case of relapsed Philadelphia chromosome-negative B-ALL where the patient underwent haploidentical HSCT using fludarabine/total body irradiation conditioning and posttransplant cyclophosphamide. Successful engraftment was achieved without SOS development.

DOI： 10.1016/j.lrr.2021.100241

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Acute graft-versus-host disease (GVHD) is a systemic immune reaction in which mature T cells in the donor inoculum are abnormally activated by the host and donor antigen-presenting cells. These activated cells then attack normal host tissue after allogeneic hematopoietic stem cell transplantation (HSCT). Clinical GVHD develops when the damage exceeds the threshold for tissue tolerance. Furthermore, functional damage of hematopoietic and non-hematopoietic organs due to this acute immune response triggers the subsequent development of chronic GVHD. The endpoint of HSCT is shifting from just surviving the acute phase to having an enriched life until later years; therefore, seamless and detailed immune management is required from the acute to chronic phase after HSCT. Acute GVHD prophylaxis consisted of calcineurin inhibitors and short-term methotrexate for a long time. However, various novel immune-modulating strategies have been developed against the background of recent diversification in donor sources and changes in treatment goals. In this review, we discuss recent clinical developments in basic and clinical research regarding acute or chronic GVHD.

DOI： 10.11406/rinketsu.62.602

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Graft-versus-host disease (GVHD) is a major complication that occurs after allogeneic hematopoietic stem cell transplantation (HSCT). While the allogeneic immune response may cause GVHD, it also plays essential roles in the resultant antitumor effects and in engraftment facilitation. Therefore, the application of necessary and sufficient immune control at an appropriate time according to the condition of each individual patient is the key to successful HSCT. Recently, the landscape of HSCT has changed drastically due to the diversification of transplanted grafts and the emergence of novel immunosuppressive methods and immune-modulatory agents. In this review, we first describe the current understanding of the immune pathogenesis of acute and chronic GVHD, and then, we discuss the characterization and therapeutic intervention for GVHD after diversified HSCT.

DOI： 10.11406/rinketsu.62.1281

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

CD4+CD25+Foxp3+ regulatory T cells (Tregs) are functionally distinct subsets of mature T cells with broad suppressive activity and have been shown to play an important role in the establishment of immune tolerance after allogeneic hematopoietic stem cell transplantation (HSCT). Tregs exhibit an activated phenotype from the stage of emigration from the thymus and maintain continuous proliferation in the periphery. The distinctive feature in homeostasis enables Tregs to respond sensitively to small environmental changes and exert necessary and sufficient immune suppression; however, on the other hand, it also predisposes Tregs to be susceptible to apoptosis in the inflammatory condition post-transplant. Our studies have attempted to define the intrinsic and extrinsic factors affecting Treg homeostasis from the acute to chronic phases after allogeneic HSCT. We have found that altered cytokine environment in the prolonged post-HSCT lymphopenia or peri-transplant use of immune checkpoint inhibitors could hamper Treg reconstitution, leading to refractory graft-versus-host disease. Using murine models and clinical trials, we have also demonstrated that proper intervention with low-dose interleukin-2 or post-transplant cyclophosphamide could restore Treg homeostasis and further amplify the suppressive function after HSCT. The purpose of this review is to reconsider the distinctive characteristics of post-transplant Treg homeostasis and discuss how to harness Treg homeostasis to optimize posttransplant immunity for developing a safe and efficient therapeutic strategy.

DOI： 10.3389/fimmu.2021.713358

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 77-year-old Japanese woman who had been treated for follicular lymphoma for 8 years developed abdominal pain and intra-abdominal lymphadenopathies. Colonoscopy revealed an elevated lesion in the rectum, which presented as two humps with erosions. A diagnosis of histologic transformation of follicular lymphoma to diffuse large B-cell lymphoma was made by endoscopic biopsy. This case underscores the importance of endoscopy examinations and biopsy of newly emerged gastrointestinal lesions for the prompt diagnosis of histologic transformation, since salvage chemotherapy must be initiated quickly in such cases.

DOI： 10.18926/AMO/62775

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Potent graft-versus-tumor (GVT) effects associated with graft-versus-host disease (GVHD) might be dependent on hematologic disease type and status. However, the data regarding the impact of GVHD on transplant outcomes for patients with myelodysplastic syndrome (MDS) are limited. EXPERIMENTAL DESIGN: We retrospectively evaluated the impact of acute and chronic GVHD on transplant outcomes for a large cohort of adult patients with a low-risk (n = 1,193) and high-risk (n = 1,926) MDS treated by first allogeneic hematopoietic cell transplantation between 2001 and 2017. RESULTS: The multivariate analysis, in which development of GVHD was treated as a time-dependent covariate, showed that acute and chronic GVHD at any grade or severity did not improve overall mortality, relapse, or nonrelapse mortality (NRM) in low-risk MDS. For patients with high-risk MDS, development of limited chronic GVHD was significantly associated with lower overall mortality [HR, 0.66; 95% confidence interval (CI), 0.50-0.86; P = 0.002]. This is probably due to that the reduced risk of relapse with grade III-IV acute GVHD (HR, 0.41; 95% CI, 0.25-0.65; P = 0.0002), or limited (HR, 0.57; 95% CI, 0.39-0.83; P = 0.003) or extensive (HR, 0.56; 95% CI, 0.41-0.77; P = 0.0004) chronic GVHD was offset by increased NRM with grade III-IV acute GVHD or extensive chronic GVHD in high-risk MDS. CONCLUSIONS: These data demonstrated a survival benefit of the graft-versus-MDS effect is present only in high-risk MDS patients with limited chronic GVHD.See related commentary by Eckel and Deeg, p. 6404.

DOI： 10.1158/1078-0432.CCR-20-1104

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We herein report four patients with desquamative esophagitis that developed one to nine days after peripheral blood stem cell transplantation (PBSCT). Three patients underwent allogeneic PBSCT for leukemia, and the other underwent autologous PBSCT for pineoblastoma. Esophagogastroduodenoscopy revealed mucosal sloughing and fresh blood in the esophagus. Fasting and intravenous proton pump inhibitor therapy in addition to blood transfusion improved the esophageal lesions within five to seven days in three patients. These cases indicate that desquamative esophagitis can occur in patients who receive hematopoietic stem cell transplantation. Although blood transfusions may be required, it can be resolved within seven days.

DOI： 10.2169/internalmedicine.4977-20

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

IgG4-producing marginal zone B-cell lymphomas (MZLs) have been recently proposed as a subtype of MZLs. Despite the abundant literature on pathophysiological features of this type of lymphoma, only a few retrospective studies pertaining to the treatment outcomes have been reported, and its prognosis remains unclear. We retrospectively analyzed seven patients with IgG4-producing MZLs diagnosed at our institute, with specific reference to treatment and outcomes. The median age was 69.0 years (55-79), and all were males. The median follow-up period was 66.6 months (8-121). All patients had localized disease; four patients had tumors of the ocular adnexa, whereas two had retroperitoneal tumors. Five patients were treated with irradiation (30 Gy/15 fr) (n = 4) or surgery (n = 1), resulting in tumor reduction. Two patients were treated by chemotherapy or irradiation. Among them, one commenced rituximab monotherapy, which led to an inadequate reduction of the tumor. Subsequent irradiation induced complete response (CR). The other patient experienced repeated relapses during follow-up and finally achieved CR by combination chemotherapy. Treatment was well tolerated in all cases, and none of the patients showed disease progression at the last follow-up visit. Our results indicate that the standard treatments for MZLs are generally appropriate for IgG4-producing MZL.

DOI： 10.1007/s12185-020-02968-w

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hematological diseases after solid organ transplant (SOT) are an emerging issue as the number of long-term SOT survivors increases. Expertise in managing patients requiring allogeneic hematopoietic stem cell transplantation (HSCT) after SOT from independent donors is needed; however, clinical reports of HSCT after SOT are limited, and the feasibility and risk are not well understood. In particular, HSCT in prior lung transplant recipients is thought to be complicated as the lung is immunologically distinct and is constantly exposed to the surrounding environment. Herein, we describe a case of successful HSCT in a patient with myelodysplastic syndromes who had previously received a lung transplant from a deceased donor for bronchiolitis obliterans syndrome. Reports about cases of HSCT after lung transplant are quite rare; thus, we discuss the mechanisms of immune tolerance through the clinical course of our case. This case suggests that HSCT after SOT can be considered a therapeutic option in cases where the transplanted organ is functionally retained and the hematological disease is in remission.

DOI： 10.1007/s12185-020-02967-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Breast involvement of Adult T-cell leukemia-lymphoma (ATLL) is extremely rare, and the data on the characteristics are limited. We herein describe a 49-year-old woman who presented with skin involvement of ATLL. Positron emission tomography/computed tomography showed bilateral breast lesions. Although the patient once achieved a complete metabolic response, a relapse of her ATLL occurred. The patient received subsequent allogeneic hematopoietic stem cell transplantation (HSCT). To our knowledge, only four cases of ATLL with breast involvement have previously been reported, and the prognoses have generally been poor. Breast lesions of ATLL have aggressive features, and intensive systemic chemotherapy and HSCT are required to improve survival.

DOI： 10.2169/internalmedicine.5077-20

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We conducted a multicenter study on anti-programmed cell death-1 monoclonal antibodies (anti-PD-1 mAbs) before/after allogeneic hematopoietic cell transplantation (allo-HCT) for Hodgkin lymphoma. Anti-PD-1 mAbs were administered to 25 patients before allo-HCT and to 20 after allo-HCT. In pre-allo-HCT setting, the median interval from the last administration to allo-HCT was 59 days. After allo-HCT, 12 patients developed non-infectious febrile syndrome requiring high-dose corticosteroid. The cumulative incidences of grade II-IV acute graft-versus-host disease (aGvHD) were 47.1%. Eight patients who had GvHD prophylaxis with post-transplant cyclophosphamide (PTCy) had less frequent aGvHD (grade II-IV, 14.6% versus 58.8%; P = 0.086). The 1 year overall survival (OS), relapse/progression, and non-relapse mortality rates were 81.3%, 27.9%, and 8.4%. In post-allo-HCT setting, the median interval from allo-HCT to the first administration was 589 days. The overall and complete response rates were 75% and 40%. At 100 days after anti-PD-1 therapy, the cumulative incidences of grade II-IV aGvHD, moderate-to-severe chronic GvHD, and grade 3-4 immune-related toxicity were 15.0%, 30.0%, and 30.0%. While the 1 year relapse/progression rate was 47.4%, the 1 year OS probability was 89.7%. In conclusion, immune-related complications were frequent despite modifications of GvHD prophylaxis or anti-PD-1 mAb dosing. In anti-PD-1-mAb-pretreated patients, PTCy-based GvHD prophylaxis may be effective.

DOI： 10.1007/s12185-020-02960-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

To investigate which reduced-intensity conditioning (RIC)/reduced-toxicity conditioning (RTC) is superior for umbilical cord blood transplantation (UCBT) for lymphoid malignancies, we retrospectively compared three widely used RIC/RTC regimens: fludarabine/melphalan/total body irradiation (FM-TBI, n = 524), fludarabine/cyclophosphamide/total body irradiation (FC-TBI, n = 96), and fludarabine/busulfan/total body irradiation or melphalan (FB-based, n = 159). Among patients with acute lymphoblastic leukemia (ALL) (n = 314), there were no differences in overall survival (OS) by conditioning regimen. Among patients with malignant lymphoma (ML) (n = 465), FM-TBI and FC-TBI regimens had similar OS, whereas FB-based regimen had lower OS (hazard ratio [HR], 1.73; P < 0.01) than did FM-TBI regimen due to higher non-relapse mortality (HR, 1.72; P = 0.02). In addition, mycophenolate mofetil-containing GVHD prophylaxis was associated with better OS than methotrexate-containing GVHD prophylaxis among patients who received FM-TBI (HR, 0.65; P = 0.03) and FC-TBI (HR, 0.25; P < 0.01) regimens due to a decreased relapse risk. In summary, our results suggest that all three RIC/RTC regimens have comparable clinical outcomes in ALL, while the FM-TBI or FC-TBI regimens combined with mycophenolate mofetil-containing GVHD prophylaxis is preferable in RIC/RTC-UCBT for ML. Large prospective studies are warranted to confirm these results.

DOI： 10.1038/s41409-020-0905-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Photodynamic therapy (PDT) is an emerging treatment for various solid cancers. We recently reported that tumor cell lines and patient specimens from adult T cell leukemia/lymphoma (ATL) are susceptible to specific cell death by visible light exposure after a short-term culture with 5-aminolevulinic acid, indicating that extracorporeal photopheresis could eradicate hematological tumor cells circulating in peripheral blood. As a bridge from basic research to clinical trial of PDT for hematological malignancies, we here examined the efficacy of ALA-PDT on various lymphoid malignancies with circulating tumor cells in peripheral blood. We also examined the effects of ALA-PDT on tumor cells before and after conventional chemotherapy. With 16 primary blood samples from 13 patients, we demonstrated that PDT efficiently killed tumor cells without influencing normal lymphocytes in aggressive diseases such as acute ATL. Importantly, PDT could eradicate acute ATL cells remaining after standard chemotherapy or anti-CCR4 antibody, suggesting that PDT could work together with other conventional therapies in a complementary manner. The responses of PDT on indolent tumor cells were various but were clearly depending on accumulation of protoporphyrin IX, which indicates the possibility of biomarker-guided application of PDT. These findings provide important information for developing novel therapeutic strategy for hematological malignancies.

DOI： 10.1038/s41598-020-74174-x

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記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

To date, there are no data focusing on outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U). This study aimed to evaluate outcomes and prognostic factors in patients with MDS/MPN-U after allo-HSCT using Japanese nationwide registry data. The primary endpoint was 3-year overall survival (OS); secondary endpoints included the cumulative incidence of relapse and nonrelapse mortality (NRM). We evaluated the prognostic factors for 3-year OS by univariate analysis using the log-rank test. In our cohort of 86 patients with MDS/MPN-U, we found a 3-year OS of 48.5%, cumulative incidence of relapse of 23.7%, and NRM of 26.3%. The 3-year OS was significantly worse in patients age ≥50 years compared with those age <50 years (38.1% versus 65.0%; P = .049) and in patients with disease progression compared with those without disease progression (28.4% versus 57.2%; P = .042). Our results suggest that allo-HSCT may offer a curative option for patients with MDS/MPN-U, and that age and disease status could be important indicators in helping clinicians determine treatment options for these patients.

DOI： 10.1016/j.bbmt.2020.05.013

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Graft failure (GF) is a life-threatening complication after allogeneic stem cell transplantation (SCT). Although salvage SCTs can be performed with haploidentical donor (HID) or cord blood (CB), no study has compared the performances of these two sources. Using nationwide registration data, we compared the transplant outcomes of patients who developed GF and underwent salvage transplantation from HID (n = 129) and CB (n = 570) from 2007 to 2016. The HID group demonstrated better neutrophil recovery (79.7 vs. 52.5% at 30 days, P < 0.001). With a median follow-up of 3 years, both groups demonstrated similar overall survival (OS) and nonrelapse mortality (NRM; 1-year OS, 33.1 vs. 34.6% and 1-year NRM, 45.1 vs. 49.8% for the HID and CB groups). After adjustments for other covariates, OS did not differ in both groups. However, HID was associated with a lower NRM (hazard ratio, 0.71; P = 0.038) than CB. The incidence of acute graft-versus-host disease (GVHD)-related deaths was significantly higher in the HID group, although infection-related deaths were observed more frequently in the CB group. HID may be a promising salvage SCT option after GF due to its faster engraftment and low NRM.

DOI： 10.1038/s41409-020-0821-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Post-transplant lymphoproliferative disorder (PTLD) is one of the most serious complications of allogeneic hematopoietic stem cell transplantation (HSCT). Rituximab is effective for PTLD; however, rituximab can produce adverse effects, including hypogammaglobulinemia. Here, we present the case of an 18-year-old female with refractory cytopenia of childhood who developed persistent selective hypogammaglobulinemia with low immunoglobulin G (IgG) 2 and IgG4 levels and monoclonal protein after rituximab therapy against probable PTLD. Despite B-cell recovery, the serum IgG levels gradually declined, reaching < 300 mg/dL at 33 months after rituximab treatment. In addition, class-switched memory (CD27 + IgD -) B cells were limited in phenotypic analysis. These findings suggest that peri-HSCT rituximab may contribute to an abnormal B-cell repertoire induced by impaired immunoglobulin class switch.

DOI： 10.1007/s12185-020-02886-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pulmonary alveolar proteinosis (PAP) is an uncommon lung disorder characterized by the excessive accumulation of surfactant-derived lipoproteins in the pulmonary alveoli and terminal bronchiole. Secondary PAP associated with primary myelofibrosis (PMF) is extremely rare, and to our knowledge, no autopsy case has been reported. We herein report an autopsy case of secondary PAP occurring in a patient with PMF who was treated with the Janus kinase 1/2 inhibitor ruxolitinib. We confirmed a diagnosis of PAP with complications based on the pathological findings at the autopsy. Notably, this case might suggest an association between ruxolitinib treatment and PAP occurrence.

DOI： 10.2169/internalmedicine.4082-19

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

This study aimed to investigate allogeneic hematopoietic cell transplantation (HCT) outcomes and risk factors in adult patients with therapy-related myeloid neoplasm (t-MN) using Japanese registry data. Between 2002 and 2012, a total 12,169 adult patients underwent HCT for acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), or chronic myelomonocytic leukemia (CMML). Of these, 565 with t-MN were identified. The median patient age was 54 years (range, 16 to 80 years). Three hundred and ninety-eight patients had AML, 154 had MDS, and 13 had CMML. Lymphoma and breast cancer were the major previous malignancies. Favorable karyotypes were detected in 84 patients, and poor karyotypes were identified in 235. Two-thirds (66%) of the patients were in nonremission at HCT. Overall survival at 3 years in patients with t-MN was 31% (95% confidence interval [CI], 27% to 35%), equivalent to that in those with secondary MN (32%; 95% CI, 30% to 34%), and 44% in the de novo cohort (95% CI, 43% to 45%). The cumulative incidence of relapse and nonrelapse mortality at 3 years was 40% and 33%, respectively. The outcomes of HCT for t-MN in Japan were comparable to those in large-scale studies in Europe and the United States.

DOI： 10.1016/j.bbmt.2020.04.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication after hematopoietic stem cell transplantation (HSCT). Several studies of risk factors for PTLD have been reported; however, the probability of, and risk factors for, PTLD in patients with lymphoma is unknown. Japanese nationwide transplant registry data from 5270 patients with lymphoma after allogeneic HSCT were analyzed. Mature B-cell, T/NK-cell, and T-cell lymphoblastic subtypes accounted for 49%, 26%, and 9.6% of lymphoma cases, respectively. Rituximab was used in 1678 lymphoma patients, most of whom (89%) received HSCT for mature B-cell lymphoma. Thirty-one patients with lymphoma developed PTLD, representing a probability of 0.77% at 2 years post-HSCT, which did not differ significantly from that in patients with other diseases (P = .98). Year of HSCT after 2010 (hazard ratio [HR] = 5.6, 95% confidence interval [CI], 1.48-21.3), antithymocyte globulin (ATG) use in the conditioning regimen (HR = 4.5, 95% CI, 1.61-12.5), and no rituximab use before HSCT (HR = 3.2, 95% CI, 1.26-7.90) were identified as risk factors for PTLD. Probabilities of PTLD at 1 year post-HSCT according to rituximab and ATG use were 0.23% (rituximab+, ATG-), 0.75% (rituximab-, ATG-), 1.25% (rituximab+, ATG+), and 3.53% (rituximab-, ATG+). Regarding lymphoma subtypes, patients with mature B-cell lymphoma had the lowest incidence of PTLD (0.35% at 2 years). Among high-risk patients receiving ATG, the mortality rate due to infection was elevated in those previously treated with rituximab (22%) relative to those without (14%); however, the difference was not significant (P = .10). Rituximab use before HSCT significantly reduces the risk of PTLD. Adding rituximab to the conditioning regimen is potentially a good strategy to prevent the development of PTLD in high-risk patients.

DOI： 10.1002/hon.2714

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記述言語：英語  

DOI： 10.1038/s41409-019-0542-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The optimal intensity of conditioning regimen may be dependent on not only age and comorbidities but also disease characteristics and risk of relapse after allogeneic hematopoietic cell transplantation (HCT). We, therefore, analyzed the transplant outcomes of 840 adult patients with cytogenetically poor-risk acute myeloid leukemia (AML) in first complete remission (CR1) who received first allogeneic HCT with either myeloablative conditioning (MAC; n = 652) or reduced-intensity conditioning (RIC; n = 188) between 2006 and 2017. The median age at HCT was 50.5 years (range: 16 to 77 years). The multivariate analysis showed that patients receiving MAC had a significantly higher overall survival and lower leukemia-related mortality than those receiving RIC (P = .011 and P = .025, respectively). In the subgroup analysis, these results applied to patients aged 16 to 59 years, with HCT-comorbidity index scores ≥3, and with cytogenetic remission. Among MAC regimens, there was a trend for worse survival and nonrelapse mortality with the busulfan/fludarabine-based regimen compared with the total body irradiation (TBI) ≥8 Gy-based regimen (P = .082 and P = .062, respectively), whereas the busulfan/cyclophosphamide-based regimen and the fludarabine/melphalan-based regimen had similar outcomes with the TBI-based regimen. These data suggest that MAC is preferable to RIC for patients with cytogenetically poor-risk AML undergoing allogeneic HCT in CR1.

DOI： 10.1016/j.bbmt.2019.09.025

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Mixed chimerism (MC) and/or secondary graft failure (SGF) with recipient- or donor-type chimerism is a major obstacle in allogeneic transplantation for aplastic anemia (AA). From a registry database in Japan, patients with AA age >15 years who underwent a first allogeneic bone marrow or peripheral blood stem cell transplantation between 2000 and 2014 and achieved engraftment were included in this study. MC that did not require either granulocyte-colony stimulating factor (G-CSF) or transfusion support (group 1), MC (not SGF) that required G-CSF and/or transfusion support (group 2), SGF with MC or complete recipient-type chimerism (group 3), and SGF with complete donor-type chimerism (group 4) developed in 26, 16, 19, and 17 patients, respectively. The overall median duration of follow-up for survivors was 1727 days. The overall survival (OS) was 90.4% at 1 year and 83.5% at 5 years in patients without MC or SGF (n = 340), which was not different from the OS in groups 1 and 2. However, inferior OS was observed in group 3 (1 year, 52.1%; 5 years, 52.1%) and group 4 (1 year, 82.4%; 5 years, 56.3%). In multivariate analyses, the use of fludarabine (Flu) and the absence of irradiation in conditioning were associated with the development of SGF with MC or complete recipient-type chimerism, and the use of Flu in conditioning was associated with SGF with complete donor-type chimerism. In conclusion, the use of Flu may affect the occurrence of SGF with both recipient-type and donor-type chimerism.

DOI： 10.1016/j.bbmt.2019.10.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Cross-matched platelet (cross-matched PLT) transfusion is effective for immune-mediated platelet transfusion refractoriness (PTR), but is more costly and time-consuming for physical cross-match than using standard PLT units. Recent studies have reported the utility of human leucocyte antigens (HLA) virtual cross-matched PLT (HLA-matched PLT) that is defined as HLA-A/B matched or no antibody against donor-specific antigen. Here, we evaluated the effect of HLA-matched PLTs for PTR in post hematopoietic stem cell transplant (HSCT) recipients. STUDY DESIGN AND METHODS: Our study included a total of 241 PLTs in 16 patients who underwent HSCT at Okayama University Hospital between 2010 and 2017, receiving either HLA-matched or cross-matched PLTs. We calculated the 24-hour corrected count increments (CCI-24) to evaluate the effect of PLTs. A CCI-24 ≥ 4500 was considered to be a successful transfusion. RESULTS: We analyzed 139 cross-matched PLTs and 102 HLA-matched PLTs. In the immune-mediated PTR, the rate of successful transfusion was 60.5% for cross-matched PLT and 63.4% for HLA-matched PLT (p = 0.825). On the other hand, the median CCI-24 for cross-matched PLT transfusions and HLA-matched PLT transfusions were 1856 and 5824 (p < 0.001), with a success rate of 28.1 and 54.1% in cases with non-immune-mediated PTR, respectively (p = 0.001). CONCLUSION: The effectiveness of HLA-matched PLT is not inferior to cross-matched PLT. This result indicates that physical cross-match can be omitted in post HSCT PTR.

DOI： 10.1111/trf.15664

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Adult T-cell leukemia/lymphoma (ATL), an aggressive type of T-cell malignancy, is caused by the human T-cell leukemia virus type I (HTLV-1) infections. The outcomes, following therapeutic interventions for ATL, have not been satisfactory. Photodynamic therapy (PDT) exerts selective cytotoxic activity against malignant cells, as it is considered a minimally invasive therapeutic procedure. In PDT, photosensitizing agent administration is followed by irradiation at an absorbance wavelength of the sensitizer in the presence of oxygen, with ultimate direct tumor cell death, microvasculature injury, and induced local inflammatory reaction. This review provides an overview of the present status and state-of-the-art ATL treatments. It also focuses on the photodynamic detection (PDD) of hematopoietic malignancies and the recent progress of 5-Aminolevulinic acid (ALA)-PDT/PDD, which can efficiently induce ATL leukemic cell-specific death with minor influence on normal lymphocytes. Further consideration of the ALA-PDT/PDD system along with the circulatory system regarding the clinical application in ATL and others will be discussed. ALA-PDT/PDD can be promising as a novel treatment modality that overcomes unmet medical needs with the optimization of PDT parameters to increase the effectiveness of the tumor-killing activity and enhance the innate and adaptive anti-tumor immune responses by the optimized immunogenic cell death.

DOI： 10.3390/cancers12020335

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a significant cause of morbidity and mortality. Regulatory T cells (Tregs) are critical mediators of immune tolerance after allo-HSCT. Clinical studies have indicated that programmed cell death 1 (PD-1) blockade before allo-HSCT involves a risk of severe GVHD. However, the mechanisms underlying GVHD induction resulting from PD-1 blockade remain unclear. We investigated the impact of PD-1 expression of donor T cells on T-cell reconstitution and GVHD using murine models. We first demonstrated that inhibition of PD-1 signaling induced aggressive expansion of CD4+ conventional T cells; however, Tregs could not maintain expansion because of high susceptibility to apoptosis, resulting in discordant immune recovery and subsequent development of severe GVHD. We then evaluated the impact of posttransplantation cyclophosphamide (PTCy) on abnormal T-cell reconstitution after PD-1 blockade. PTCy efficiently ameliorated GVHD after transplantation from a PD-1-/- donor and extended overall survival by safely regulating the proliferation and apoptosis of T-cell subsets. Notably, in the first 2 weeks after administration of PTCy, Tregs regained their ability to continuously proliferate, resulting in well-balanced reconstitution of donor T-cell subsets. In conclusion, the influence of PD-1 blockade differed within T-cell subsets and caused unbalanced reconstitution of T-cell subsets, resulting in severe GVHD. PTCy successfully restored T-cell homeostasis and ameliorated GVHD induced by PD-1-/- donor T cells. These findings may help explain the pathophysiology behind the observation that PTCy may mitigate the incidence and impact of GVHD associated with prior exposure to PD-1 blockade.

DOI： 10.1182/bloodadvances.2019000134

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The significance of low-dose total body irradiation (TBI) in HLA-mismatched reduced-intensity conditioning stem cell transplantation (RICT) remains unknown. We, retrospectively, evaluated the impact of low-dose TBI in patients with hematological malignancies who received first RICT from ≥1 antigen-mismatched donors between 2004 and 2014. Of the 575 patients, 361 patients received low-dose TBI (2 or 4 Gy). There were no significant differences in neutrophil engraftment or platelet recovery between TBI and non-TBI groups. The benefit of low-dose TBI on neutrophil engraftment was not observed in any subgroups. Low-dose TBI was not associated with decreased secondary graft failure. Suppressed mixed chimerism and autologous hematopoiesis by low-dose TBI was observed. There were no significant differences in cumulative incidences of acute GVHD or nonrelapse mortality rates in either group; however, low-dose TBI improved overall survival (OS), especially in patients with high-risk disease, multi-HLA mismatch, and fludarabine/busulfan conditioning. Multivariate analysis demonstrated that low-dose TBI was an independent prognostic factor for OS. Compared with the non-TBI group, 4 Gy TBI, but not 2 Gy TBI, was associated with increased acute GVHD and reduced relapse. These findings suggest that low-dose TBI may be beneficial for patients at high risk for relapse in HLA-mismatched RICT.

DOI： 10.1038/s41409-019-0434-3

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記述言語：英語  

DOI： 10.1007/s12185-019-02659-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Mogamulizumab (Mog), a humanized anti-CCR4 antibody, provides an important treatment option for relapsed/refractory adult T cell leukemia/lymphoma. However, administration of Mog before allogenic hematopoietic stem cell transplantation has been reported to be a risk factor for severe acute graft-versus-host disease (GVHD). The etiological hypothesis is Mogamulizumab may eradicate CCR4-positive regulatory T cells (Tregs). Theoretically, Treg homeostasis and course of GVHD can be affected by plasma exchange (PE) with decreasing plasma Mog concentration. Here, we present a case of severe acute GVHD after pretransplantation Mog, in which PE was performed for liver failure. As a result, plasma Mog concentration was decreased but it did not lead to the prompt elevation of Treg levels in peripheral blood and clinical responses of GVHD were limited to partial remission. Our case suggests that recovery of donor-derived Treg in the acute phase after HSCT is multifactorial and the single procedure of PE-based Mog depletion does not necessarily warrant the quick restoration of Treg homeostasis.

DOI： 10.1016/j.transci.2019.05.011

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The use of granulocyte colony-stimulating factor-mobilized peripheral blood stem cells (PBSCs) and sex-mismatched hematopoietic cell transplantation (HCT), especially with female donors and male recipients (FtoM), is known to be associated with an increased risk of chronic graft-versus-host disease (GVHD) compared with transplantation with bone marrow (BM). This raises the question of whether the use of PBSCs in FtoM HCT might affect allogeneic responses, resulting in fatal complications. Using a Japanese transplantation registry database, we analyzed 1132 patients (FtoM, n = 315; MtoF, n = 260; sex-matched, n = 557) with standard-risk diseases who underwent HCT with an HLA-matched related donor without in vivo T-cell depletion between 2013 and 2016. The impact of PBSC vs BM on transplantation outcomes was separately assessed in FtoM, MtoF, and sex-matched HCT. Overall survival (OS) and nonrelapse mortality (NRM) at 2 years post-HCT were significantly worse in patients with PBSCs vs those with BM in FtoM HCT (2-year OS, 76% vs 62%; P = .0084; 2-year NRM, 10% vs 21%; P = .0078); no differences were observed for MtoF or sex-matched HCT. Multivariate analyses confirmed the adverse impact of PBSCs in FtoM HCT (hazard ratio [HR] for OS, 1.91; P = .025; HR for NRM, 3.70; P = .0065). In FtoM HCT, patients with PBSCs frequently experienced fatal GVHD and organ failure. In conclusion, the use of PBSCs in FtoM HCT was associated with an increased risk of NRM in the early phase, resulting in inferior survival. This suggests that, when we use female-related donors for male patients in HCT, BM may result in better outcomes than PBSCs.

DOI： 10.1182/bloodadvances.2019000077

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記述言語：日本語   出版者・発行元：(一社)日本リンパ網内系学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Second allogeneic stem cell transplantation (allo-SCT) is a potentially curative therapy for patients who relapse after first allo-SCT. Human leukocyte antigen (HLA)-haploidentical related donors provide the broad opportunity to conduct second SCT at the appropriate time, but the efficacy of second SCT from haploidentical donors after relapse has not been established. We retrospectively analyzed the records of 33 patients who underwent second SCT. Twenty patients underwent haplo-SCT with low-dose antithymocyte globulin (ATG), and the other 13 patients underwent conventional- SCTs, including HLA-matched related peripheral blood, unrelated bone marrow or cord blood. Three years after the second SCT, the overall survival (OS) and progression-free survival (PFS) of all patients were 32.5% and 23.9%. Multivariate analyses indicated that non-complete response at second SCT, less than 1-year interval to relapse after first- SCT, and total score ≥ 3 on the hematopoietic cell transplantation-specific comorbidity index were significantly associated with a lower PFS rate. The haplo- and conventional- SCT groups showed equivalent results regarding OS, PFS, cumulative incidences of relapse, non-relapse mortality and graft-versus-host disease. The neutropenic period after transplantation was significantly shorter in haplo- SCT than conventional- SCT (10.5 days vs. 16 days, p=0.001). Our analysis revealed that haplo-SCT could be an alternative therapeutic option for relapsed patients after first SCT.

DOI： 10.18926/AMO/56652

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The number of patients who are successfully discharged from the intensive care unit (ICU) after hematopoietic stem cell transplantation (HSCT) remains limited. Most previous studies have evaluated short-term outcomes using ICU mortality; there have been comparatively fewer reports of long-term outcomes. We retrospectively analyzed 39 HSCT patients admitted to the ICU for the first time between April 2008 and July 2014. Performance status was evaluated in four long-term survivors in July 2016. Median age at ICU admission was 54 years (range 30-68). In total, 33 patients (70.2%) required mechanical ventilation and 31 patients (66%) required dialysis. The median OS from first ICU admission was 41 days (95% confidence interval [CI]: 22-64) and the 1-year survival rate was 12.8% (95% CI 4.7-25.2). No statistically significant factors were associated with short-term outcomes. Among long-term outcomes, a second or subsequent HSCT and neutropenia at ICU admission were significant risk factors. Four of 10 ICU survivors have survived with good performance status for a median of 1994 (1203-2633) days. Our results suggest that the number of prior transplants and neutropenia at ICU admission may influence OS.

DOI： 10.1007/s12185-018-2536-x

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記述言語：英語   出版者・発行元：(一社)日本血液学会-東京事務局  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We evaluated the efficacy and safety of switching to nilotinib in CML-CP patients who had achieved MMR with continuous detectable BCR-ABL1 transcript levels after long-term imatinib treatment. Patients who had achieved MMR, but not deep molecular response (DMR), after > 18 months from the initiation of imatinib received nilotinib 400 mg twice daily for up to 24 months. BCR-ABL1 transcript levels were assessed every 3 months. Thirty-eight patients with a median age of 57.5 years (range 22-76 years) were evaluated. Twenty-seven patients completed 24 months of nilotinib treatment; 11 discontinued nilotinib due to retraction of consent (three patients), loss of MMR (1), intolerance (3) or AEs (5). Twenty patients [52.6%, (90% CI 38.2-66.7%)] achieved DMR. The cumulative incidence of achieving DMR by the time of 3, 6, 9, 12, 15, 18, and 21 months was 22.9, 37.7, 47.0, 53.7, 53.7, 53.7, and 53.7%, respectively. Adverse events were consistent with those reported in other nilotinib studies. Patients experienced each of the following cardiovascular complications: atrial fibrillation (G2), chest tightness and dyspnea (G1), myocardial infarction (G2) and heart failure (G3) (n = 1 for each complication). This study indicates nilotinib achieves strong, rapid induction of DMR for patients who achieved MMR after long-term imatinib therapy.

DOI： 10.1007/s12185-018-2401-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Creatinine clearance rate (Ccr) is a more accurate indicator of renal function than serum creatinine. Data are sparse regarding the prognostic value of renal impairment calculated using Ccr in patients who undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT). We performed a retrospective analysis of 185 patients who underwent allo-HSCT. These patients were divided into two groups by Ccr (ml/min) before transplantation; one showed normal renal function (Ccr ≥ 60, n = 156) and the other showed mild renal dysfunction (30 ≤ Ccr < 60, n = 29), and transplant outcomes were compared between the groups. We observed no significant difference between the groups in terms of clinical characteristics other than age, estimated glomerular filtration rate, serum creatinine, Ccr predicted by Cockcroft-Gault formula, primary disease, and conditioning intensity. With respect to transplant outcomes, no significant difference was observed in overall survival, relapse, or non-relapse mortality between the two groups. Multivariate analysis demonstrated that 30 ≤ Ccr < 60 before allo-HSCT was not an independent prognostic factor for transplant outcome. In conclusion, these results suggest that patients with mild renal dysfunction, defined as 30 ≤ Ccr < 60 ml/min, can safely undergo allo-HSCT. However, a larger series of patients is needed to evaluate the impact of mild renal dysfunction before allo-HSCT in more detail.

DOI： 10.1007/s12185-017-2398-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although the CD34+ cell dose in allogeneic peripheral blood stem cell transplantation (PBSCT) is considered to be associated with transplantation outcomes, a lower acceptable threshold has not been defined. We retrospectively analyzed 2919 adult patients with hematologic malignancies who underwent related PBSCT in Japan between 2001 and 2014. According to the number of CD34+ cells in the graft, we categorized 2494 patients in the standard group (2 to 5 × 106 cells/kg), 377 patient in the low group (1 to 2 × 106 cells/kg), and 48 patients in the very low group (<1 × 106 cells/kg). Compared with the standard group, the low and very low groups showed delayed neutrophil recovery (93.8%, 89.5%, and 78.3%, respectively at day +28; P < .001) and platelet recovery (69.3%, 53.0%, and 45.5%, respectively at day +28; P < .001). The 2-year overall survival (OS) in the 3 groups was 45.5%, 45.3%, and 29.8%, respectively, with inferior survival in the very low group. However, a higher percentage of high-risk patients may account for the inferior survival in the very low group, and no significant difference in OS was found in a multivariate analysis. There were no differences in relapse, nonrelapse mortality, or the development of graft-versus-host disease among the 3 groups. In conclusion, allogeneic PBSCT with low CD34+ cell doses of 1 to 2 × 106 cells/kg gives acceptable results, whereas further investigations are needed to evaluate the effects of lower doses of <1 × 106 cells/kg owing to the smaller number and the higher percentage of patients with adverse prognostic factors in this cohort.

DOI： 10.1016/j.bbmt.2017.10.043

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapeutic option for patients with chronic myelomonocytic leukemia (CMML). We retrospectively compared the post-transplantation outcomes of 159 patients with CMML who underwent allo-HSCT using 4 types of donor sources: HLA-matched related donor graft, unrelated bone marrow (U-BM), unrelated cord blood (U-CB), and HLA-mismatched related donor graft. The median patient age at allo-HSCT was 54 years (range, 16 to 75 years). In multivariate analyses, the use of HLA-matched related donor grafts correlated with better overall survival than U-BM (hazard ratio [HR], 2.05; 95% confidence interval [CI], 1.21 to 3.48; P = .008), U-CB (HR, 3.80; 95% CI, 2.07 to 6.95; P < .001), or HLA-mismatched related donor grafts (HR, 6.18; 95% CI, 2.70 to 14.15; P < .001). Mortality after the relapse or progression of CMML did not significantly differ among the 4 types of donor source. Transplantation-related mortality was highest in recipients of U-CB (HR, 3.32; 95% CI, 1.33 to 8.26; P = .010). In patients with CMML, allo-HSCT using an alternative donor may contribute to durable remission; however, further improvements in transplantation-related mortality are required for this type of transplantation.

DOI： 10.1016/j.bbmt.2017.11.016

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 52-year-old man suffered from progressive multifocal leukoencephalopathy (PML) after human leukocyte antigen (HLA)-haploidentical transplantation with post-transplantation cyclophosphamide (PTCY). Mirtazapine, mefloquine, and cytarabine failed to improve his symptoms, and he finally died 4.5 months after PML onset. This is the first case report of a patient with PML after HLA-haploidentical transplantation with PTCY. Although T-cell replete HLA-haploidentical transplantation with PTCY has enabled early immune reconstitution, PML should be considered if a patient's mental condition deteriorates.

DOI： 10.1111/tid.12850

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記述言語：日本語   出版者・発行元：(一社)日本輸血・細胞治療学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

CD4+CD25+Foxp3+ Treg is a functionally distinct subset of mature T cells with broad suppressive activity and has been shown to play an important role in the establishment of immune tolerance after HSCT. Altered cytokine environment in post-HSCT lymphopenia with a relative functional deficiency of IL-2 could hamper the reconstitution of Treg, leading to refractory GVHD. Based on the theory of low-dose IL-2 in which Treg can be selectively stimulated through the high-affinity IL-2 receptor, clinical studies have been conducted and demonstrated that low-dose IL-2 administration can restore Treg homeostasis and promote the expansion of this subset on the polymorphic processes of Treg reconstitution after HSCT. The new therapeutic indication of IL-2 for immune tolerance has launched in the field of HSCT and is spreading to the other fields including the treatment for autoimmune diseases. To further extend the indication of low-dose IL-2 to more patients with various immunological problems, the optimization of the timing and dosing of IL-2 intervention and the concomitant immune suppressive therapy according to each patient-based assessment are to be desired in the near future. Further prospective studies may facilitate the development of novel therapeutic algorithms for the effective and safe induction of immune tolerance after HSCT.

DOI： 10.1007/s12185-017-2386-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

CD4+Foxp3+ regulatory T cells (Tregs) play a central role in the maintenance of immune tolerance after hematopoietic stem cell transplantation. We previously reported that low-dose interleukin-2 (IL-2) therapy increased circulating Tregs and improved clinical symptoms of chronic graft-versus-host-disease (cGVHD); however, the mechanisms that regulate Treg homeostasis during IL-2 therapy have not been well studied. To elucidate these regulatory mechanisms, we examined the role of inhibitory coreceptors on Tregs during IL-2 therapy in a murine model and in patients with cGVHD. Murine studies demonstrated that low-dose IL-2 selectively increased Tregs and simultaneously enhanced the expression of programmed cell death 1 (PD-1), especially on CD44+CD62L+ central-memory Tregs, whereas expression of other inhibitory molecules, including CTLA-4, LAG-3, and TIM-3 remained stable. PD-1-deficient Tregs showed rapid Stat5 phosphorylation and proliferation soon after IL-2 initiation, but thereafter Tregs became proapoptotic with higher Fas and lower Bcl-2 expression. As a result, the positive impact of IL-2 on Tregs was completely abolished, and Treg levels returned to baseline despite continued IL-2 administration. We also examined circulating Tregs from patients with cGVHD who were receiving low-dose IL-2 and found that IL-2-induced Treg proliferation was promptly followed by increased PD-1 expression on central-memory Tregs. Notably, clinical improvement of GVHD was associated with increased levels of PD-1 on Tregs, suggesting that the PD-1 pathway supports Treg-mediated tolerance. These studies indicate that PD-1 is a critical homeostatic regulator for Tregs by modulating proliferation and apoptosis during IL-2 therapy. Our findings will facilitate the development of therapeutic strategies that modulate Treg homeostasis to promote immune tolerance.

DOI： 10.1182/blood-2016-09-741629

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Azacitidine (Aza) and donor lymphocyte infusion (DLI) therapy has recently been reported as an effective salvage therapy for relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Despite the high response rate and relatively long period of remission, most patients relapse again. The immunologic mechanism of the response and limited efficacy remain unknown. CASE REPORT: Aza + DLI therapy was performed for a patient with therapy-related MDS (t-MDS), who had relapsed after allogeneic peripheral blood stem cell transplantation. We observed a powerful graft-versus-leukemia (GVL) effect accompanied by an evident Wilms tumor antigen 1 (WT1)-specific CD8 T-cell response. Remission continued for 15 months, but finally the patient relapsed. The kinetics of the WT1-specific CD8 T cells were inversely associated with WT1 messenger RNA (mRNA), suggesting a WT1-driven GVL effect. DISCUSSION: A difference of T-cell phenotype between the whole T cells and the WT1-specific CD8 T cells was observed. It is of note that the memory phenotype of the WT1-specific T cell was limited and decreased early. The immunoescape mechanism was partly supported by loss of the memory phenotype due to failure of expansion and differentiation. CONCLUSION: Our data suggested that a WT1-specific T-cell response at least partly contributes to the GVL effect induced by Aza + DLI. A strategy for maximizing and maintaining the memory phenotype of the CTL may be required for durable remission.

DOI： 10.1016/j.jcyt.2016.12.007

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is one important treatment option for patients with aggressive adult T-cell leukemia/lymphoma (ATLL). Mogamulizumab (anti-CCR4 monoclonal antibody; Mog) was recently approved as a treatment for ATLL in Japan. Major concerns exist about the possible adverse effects of pretransplantation Mog because Mog depletes regulatory T cells for several months. We assessed the impact of pretransplantation Mog on clinical outcomes after allo-HSCT. PATIENTS AND METHODS: We included 996 allo-HSCT recipients age 70 years or younger with aggressive ATLL who were given the diagnosis between 2000 and 2013 and who received intensive chemotherapy by multiple chemotherapeutic drugs as first-line therapy. Before allo-HSCT, 82 patients received Mog with a median interval of 45 days from the last Mog to allo-HSCT. RESULTS: Pretransplantation Mog was associated with an increased risk of grade 3 to 4 acute graft-versus-host disease (GVHD; relative risk, 1.80; P < .01) and refractoriness to systemic corticosteroid for acute GVHD (relative risk, 2.09; P < .01). One-year cumulative incidence of nonrelapse mortality was significantly higher in patients with pretransplantation Mog compared with those without (43.7% v 25.1%; P < .01). The probability of 1-year overall survival was also significantly inferior in patients with pretransplantation Mog compared with those without (32.3% v 49.4%; P < .01). In particular, use of Mog with intervals < 50 days to allo-HSCT was associated with a dismal clinical outcome. CONCLUSION: Pretransplantation Mog was significantly associated with an increased risk of GVHD-related mortality, which supports the relevance of CCR4-expressing Tregs after allo-HSCT in humans. In clinical practice, Mog should be cautiously used for patients with ATLL who are eligible for allo-HSCT.

DOI： 10.1200/JCO.2016.67.8250

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Chronic graft versus host disease (cGVHD) remains a major problem for long survivors after allogeneic hematopoietic stem cell transplantation (HSCT). Currently, corticosteroid therapy is effective for cGVHD as the first line therapy. However, prolonged therapy with corticosteroids causes various severe adverse events. To develop the new therapeutic strategy of cGVHD, we have launched a multicenter phase I/IIa clinical trial of low dose subcutaneous interleukin-2 (IL-2) for treatment of steroid refractory cGVHD, which is constituted of 2 sequential phases (induction phase and maitanance phase). This study will provide the new therapeutic option for patients with refractory cGVHD after allogeneic HSCT.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Transplant-associated thrombotic microangiopathy (TA-TMA) after hematopoietic stem cell transplantation (HSCT) remains a severe complication associated with underlying endothelial damage. TMA has a high mortality rate with no definite treatments and effective treatments are needed. STUDY DESIGN AND METHODS: The study objective was to retrospectively analyze the outcome of patients receiving recombinant human soluble thrombomodulin (rTM), which has cytoprotective effects against calcineurin inhibitor-induced endothelial cell damage, or other therapeutics for TA-TMA from 254 consecutive HSCT recipients between 2009 to 2014 at a single institution. We hypothesized that patients receiving rTM as a first-line treatment would receive a benefit. RESULTS: Sixteen patients were diagnosed as TA-TMA. Of these 16 patients, nine were treated with rTM (rTM group), and seven received treatment other than rTM (control group) as a first-line therapy. Seven of the nine patients in the rTM group recovered from TA-TMA without complications, but none in the control group recovered. The rTM group showed a significantly better overall survival after TA-TMA onset than did the control group (median, 123.0 days vs. 45.5 days, respectively; p = 0.045). The cumulative incidence of acute graft-versus-host disease was the same in both groups (56% vs. 57%, respectively; p = 0.52) on Day 100 after TA-TMA onset. CONCLUSION: This is the first report evaluating rTM administration for TA-TMA compared with previous treatments. Our data suggests that rTM might offer a better clinical outcome in patients with TA-TMA.

DOI： 10.1111/trf.13437

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Donor lymphocyte infusion (DLI) is used for treatment of hematologic malignancy relapse or mixed chimerism after allogeneic hematopoietic stem cell transplantation. Although graft-versus-host disease is well recognized as one of the adverse effects of DLI, there are limited reports on noninfectious pulmonary complications (NIPCs) after DLI. CASE REPORT: A 55-year-old woman with acute myeloid leukemia received DLI for conversion from recipient predominant to complete donor chimerism on Day +193 after allogeneic HSCT. Eight weeks later, she complained of dyspnea with fever; chest computed tomography revealed diffuse, bilateral, ground glass opacity and reticular appearance. She was diagnosed as having NIPC based on serum and bronchoalveolar lavage fluid (BALF) findings. She was successfully treated with prednisolone (PSL) and completely recovered. DISCUSSION: We analyzed the cell profile from the BALF and 27 cytokines and chemokines in the serum using the Bio-Plex platform. The cells consisted of recipient predominant macrophages and T cells. The serum cytokine and chemokine profile showed significant elevation of interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-α, macrophage inflammatory protein (MIP)-1α, and MIP-1β, which declined with the improvement of symptoms after initiation of PSL treatment. CONCLUSION: Inflammatory effectors by recipient cells, rather than allogeneic responses by donor cells, played an important role in the pathogenesis of NIPCs after DLI in the present case.

DOI： 10.1111/trf.13283

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記述言語：英語   出版者・発行元：AMER SOC HEMATOLOGY  

57th Annual Meeting of the American-Society-of-Hematology, Orlando, FL, DEC 05-08, 2015

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation. Recently, in addition to Th2 cells, Th1 and Th17 cells have been shown to contribute to chronic GVHD progression. IL-12 induces Th1 cells and IL-23 plays a role in stabilizing and/or amplifying Th17 cells, as well as in inducing IFN-γ/IL-17 double-producing cells. Because mAb targeting the p40 subunit common to both IL-12 and IL-23 can inhibit both IL-12R and IL-23R-mediated signaling, we investigated the effects of anti-p40 mAb on a well-defined chronic GVHD mice model. Treatment of anti-p40 mAb in allogeneic recipients significantly reduced the severity of clinical and pathological chronic GVHD. Intracellular staining revealed that IFN-γ single-positive (IL-17(-)) and IFN-γ/IL-17 double-positive cells were suppressed in anti-p40 mAb-treated allogeneic recipients compared with control recipients. The cytokine levels of IFN-γ and IL-17 were also decreased in serum from anti-p40 mAb-treated allogeneic recipients. T-bet expression of donor IL-17(+) CD4(+) T cells was reduced significantly in anti-p40 mAb-treated recipients, and this reduction in T-bet expression was associated with IL-22 production by donor T cells. These results suggested that anti-p40 mAb attenuated chronic GVHD via suppression of IFN-γ/IL-17-producing cells, and that targeting the IL-12/IL-23 pathway may represent a promising therapeutic strategy for preventing and treating chronic GVHD.

DOI： 10.4049/jimmunol.1400973

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm that leads to hyperviscosity and the risk of thrombosis. We encountered the case of a young male Filipino patient diagnosed with PV after the rupture of esophageal varices. The complete blood cell count showed a slight increase in white blood cells. An abdominal computed tomography scan disclosed splenomegaly and occlusion of the portal vein and collateral vessels. A blood examination demonstrated an increase in all three blood cell lines within three months. Based on the presence of severe hypercellularity of the bone marrow and positivity for the JAK2V617F mutation, we finally diagnosed the patient with PV.

DOI： 10.2169/internalmedicine.54.4687

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation, but its pathogenesis remains unclear. We investigated the role of the programmed death-1 (PD-1) pathway in chronic GVHD using a well-defined mouse model of B10.D2 (H-2(d)) donor to BALB/c (H-2(d)) recipients. PD-1 expression on allogeneic donor T cells was upregulated continuously in chronic GVHD development, whereas PD-L1 expression in host tissues was transiently upregulated and declined to basal levels in the late posttransplant period. Blockade of the PD-1 pathway by anti-PD-1, anti-PD-L1, or anti-PD-L2 mAbs exacerbated clinical and pathologic chronic GVHD. Chimeric mice revealed that PD-L1 expression in host tissues suppressed expansion of IL-17(+)IFN-γ(+) T cells, and that PD-L1 expression on hematopoietic cells plays a role in the development of regulatory T cells only during the early transplantation period but does not affect the severity of chronic GVHD. Administration of the synthetic retinoid Am80 overcame the IL-17(+)IFN-γ(+) T cell expansion caused by PD-L1 deficiency, resulting in reduced chronic GVHD damage in PD-L1(-/-) recipients. Stimulation of the PD-1 pathway also alleviated chronic GVHD. These results suggest that the PD-1 pathway contributes to the suppression of Th17/Th1-mediated chronic GVHD and may represent a new target for the prevention or treatment of chronic GVHD.

DOI： 10.4049/jimmunol.1400954

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

CD4 regulatory T cells play a critical role in establishment of immune tolerance and prevention of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. The recovery and maintenance of regulatory T cells is dependent on homeostatic factors including the generation of naïve regulatory T cells from hematopoietic precursor cells, the proliferation and expansion of mature regulatory T cells, and the survival of regulatory T cells in vivo. In this study, quantitation of mitochondrial apoptotic priming was used to compare susceptibility of regulatory T cells, conventional CD4 T cells and CD8 T cells to intrinsic pathway apoptosis in 57 patients after allogeneic hematopoietic stem cell transplantation and 25 healthy donors. In healthy donors, regulatory T cells are more susceptible to mitochondrial priming than conventional T cells. Mitochondrial priming is increased after hematopoietic stem cell transplantation in all T-cell subsets and particularly in patients with chronic graft-versus-host disease. Regulatory T cells express high levels of CD95 and are also more susceptible than conventional T cells to apoptosis through the extrinsic pathway. However, CD95 expression and extrinsic pathway apoptosis is not increased after hematopoietic stem cell transplantation. Decreased expression of BCL2 and increased expression of BIM, a mitochondrial cell death activator protein, in regulatory T cells contributes to increased mitochondrial priming in this T-cell subset but additional factors likely contribute to increased mitochondrial priming following hematopoietic stem cell transplantation.

DOI： 10.3324/haematol.2014.104166

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Chronic graft-versus-host disease (GVHD) remains a major late complication of allogeneic bone marrow transplantation (BMT). In a previous study, impaired thymic negative selection of the recipients permitted the emergence of pathogenic T cells that cause chronic GVHD using MHC class II-deficient (H2-Ab1 KO) B6 into C3H model and CD4(+) T cells isolated from chronic GVHD mice caused chronic GVHD when administered into the secondary recipients. In this study, we evaluated the kinetics of regulatory T cell (Treg) reconstitution in wild type B6 into C3H model. After myeloablative conditioning, host Tregs disappeared rapidly, followed by expansion of Tregs derived from the donor splenic T cell inoculum. However, the donor splenic T cell-derived Treg pool contracted gradually and was almost completely replaced by newly generated donor bone marrow (BM)-derived Tregs in the late post-transplantation period. Next, we compared the effects of cyclosporine (CSA) and mammalian target of rapamycin (mTOR) inhibitors on Treg reconstitution. Administration of CSA significantly impaired Treg reconstitution in the spleen and thymus. In contrast, BM-derived Treg reconstitution was not impaired in mTOR inhibitor-treated mice. Histopathological examination indicated that mice treated with CSA, but not mTOR inhibitors, showed pathogenic features of chronic GVHD on day 120. Mice treated with CSA until day 60, but not mTOR inhibitors, developed severe chronic GVHD followed by adoptive transfer of the pathogenic CD4(+) T cells isolated from H2-Ab1 KO into C3H model. These findings indicated that long-term use of CSA impairs reconstitution of BM-derived Tregs and increases the liability to chronic GVHD. The choice of immunosuppression, such as calcineurin inhibitor-free GVHD prophylaxis with mTOR inhibitor, may have important implications for the control of chronic GVHD after BMT.

DOI： 10.1016/j.bbmt.2013.11.018

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pulmonary complications in patients with hematological malignancies are often caused by infection but are sometimes associated with an underlying disease such as organizing pneumonia (OP). Here, we report a case of life-threatening steroid-resistant OP associated with myelodysplastic syndrome (MDS) and successfully performed allogeneic hematopoietic cell transplantation (HSCT). A 33-year-old female with refractory anemia with excess blasts-1 that had progressed from refractory anemia with ringed sideroblasts and concomitant Sweet's syndrome was admitted. Multiple pulmonary infiltrates were revealed on a chest computed tomography scan, which progressively worsened even after chemotherapy and corticosteroid therapy. No evidence of infection was observed in bronchoalveolar lavage fluid. A histological examination of a transbronchial lung biopsy specimen showed lymphocyte invasion with fibrosis, indicating that the pulmonary infiltrates were OP associated with MDS. Before transplantation, she suffered from respiratory failure and required oxygen supplementation. She developed idiopathic pneumonitis syndrome on day 61 that responded well to corticosteroid therapy, and the OP pulmonary infiltrates improved gradually after HSCT, She was discharged on day 104 and is well without recurrence of OP or MDS 2 years after HSCT.

DOI： 10.1186/2193-1801-3-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Bronchiolitis obliterans (BO) is a devastating complication of allogeneic hematopoietic stem cell transplantation (HSCT). We retrospectively studied 465 patients who underwent HSCT in the Okayama BMT Group between 2000 and 2009, and describe the detailed clinical features of 13 patients with BO. The 5-year cumulative incidence of BO was 3.43 %. The median time from transplantation to onset of BO was 15 months. In seven of the 13 patients, the primary symptom was only cough, indicating that cough was an important initial symptom for early diagnosis. The median duration from the onset of BO to the requirement of O2 supplementation was 13 months and the main cause of death was respiratory failure. History of chronic graft-versus-host disease was a significant risk factor. Furthermore, female recipients were at greater risk of BO than male recipients; however, no other previously reported risk factors were detected. It is currently difficult to prevent BO on the basis of the reported risk factors. A novel strategy for the early diagnosis and treatment of BO is required.

DOI： 10.1007/s12185-014-1556-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

CD4(+)Foxp3(+) regulatory T cells (Tregs) play a central role in the maintenance of immune tolerance after allogeneic hematopoietic stem cell transplantation. We recently reported that daily administration of low-dose interleukin-2 (IL-2) induces selective expansion of functional Tregs and clinical improvement of chronic graft-versus-host disease (GVHD). To define the mechanisms of action of IL-2 therapy, we examined the immunologic effects of this treatment on homeostasis of CD4(+) T cell subsets after transplant. We first demonstrated that chronic GVHD is characterized by constitutive phosphorylation of signal transducer and activator of transcription 5 (Stat5) in conventional CD4(+) T cells (Tcons) associated with elevated amounts of IL-7 and IL-15 and relative functional deficiency of IL-2. IL-2 therapy resulted in the selective increase of Stat5 phosphorylation in Tregs and a decrease of phosphorylated Stat5 in Tcons. Over an 8-week period, IL-2 therapy induced a series of changes in Treg homeostasis, including increased proliferation, increased thymic export, and enhanced resistance to apoptosis. Low-dose IL-2 had minimal effects on Tcons. These findings define the mechanisms whereby low-dose IL-2 therapy restores the homeostasis of CD4(+) T cell subsets and promotes the reestablishment of immune tolerance.

DOI： 10.1126/scitranslmed.3005265

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

CD40L has a well-established role in enhancing the immunostimulatory capacity of normal and malignant B cells, but a formulation suitable for clinical use has not been widely available. Like other TNF family members, in vivo and in vitro activity of CD40L requires a homotrimeric configuration, and growing evidence suggests that bioactivity depends on higher-order clustering of CD40. We generated a novel formulation of human recombinant CD40L (CD40L-Tri) in which the CD40L extracellular domain and a trimerization motif are connected by a long flexible peptide linker. We demonstrate that CD40L-Tri significantly expands normal CD19+ B cells by over 20- to 30-fold over 14 days and induces B cells to become highly immunostimulatory antigen-presenting cells (APCs). Consistent with these results, CD40L-Tri-activated B cells could effectively stimulate antigen-specific T responses (against the influenza M1 peptide) from normal volunteers. In addition, CD40L-Tri could induce malignant B cells to become effective APCs, such that tumor-directed immune responses could be probed. Together, our studies demonstrate the potent immune-stimulatory effects of CD40L-Tri on B cells that enable their expansion of antigen-specific human T cells. The potent bioactivity of CD40L-Tri is related to its ability to self-multimerize, which may be facilitated by its long peptide linker.

DOI： 10.1007/s00262-012-1331-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The fowl pox vector expressing the tumor-associated antigens, mucin-1 and carcinoembryonic antigen in the context of costimulatory molecules (rF-PANVAC) has shown promise as a tumor vaccine. However, vaccine-mediated expansion of suppressor T-cell populations may blunt clinical efficacy. We characterized the cellular immune response induced by ex vivo dendritic cells (DCs) transduced with (rF)-PANVAC. Consistent with the functional characteristics of potent antigen-presenting cells, rF-PANVAC-DCs demonstrated strong expression of mucin-1 and carcinoembryonic antigen and costimulatory molecules, CD80, CD86, and CD83; decreased levels of phosphorylated STAT3, and increased levels of Tyk2, Janus kinase 2, and STAT1. rF-PANVAC-DCs stimulated expansion of tumor antigen-specific T cells with potent cytolytic capacity. However, rF-PANVAC-transduced DCs also induced the concurrent expansion of FOXP3 expressing CD4CD25 regulatory T cells (Tregs) that inhibited T-cell activation. Moreover, Tregs expressed high levels of Th2 cytokines [interleukin (IL)-10, IL-4, IL-5, and IL-13] together with phosphorylated STAT3 and STAT6. In contrast, the vaccine-expanded Treg population expressed high levels of Th1 cytokines IL-2 and interferon-γ and the proinflammatory receptor-related orphan receptor γt (RORγt) and IL-17A suggesting that these cells may share effector functions with conventional TH17 T cells. These data suggest that Tregs expanded by rF-PANVAC-DCs, exhibit immunosuppressive properties potentially mediated by Th2 cytokines, but simultaneous expression of Th1 and Th17-associated factors suggests a high degree of plasticity.

DOI： 10.1097/CJI.0b013e31826a73de

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Dysfunction of regulatory T (Treg) cells has been detected in diverse inflammatory disorders, including chronic graft-versus-host disease (GVHD). Interleukin-2 is critical for Treg cell growth, survival, and activity. We hypothesized that low-dose interleukin-2 could preferentially enhance Treg cells in vivo and suppress clinical manifestations of chronic GVHD. METHODS: In this observational cohort study, patients with chronic GVHD that was refractory to glucocorticoid therapy received daily low-dose subcutaneous interleukin-2 (0.3×10(6), 1×10(6), or 3×10(6) IU per square meter of body-surface area) for 8 weeks. The end points were safety and clinical and immunologic response. After a 4-week hiatus, patients with a response could receive interleukin-2 for an extended period. RESULTS: A total of 29 patients were enrolled. None had progression of chronic GVHD or relapse of a hematologic cancer. The maximum tolerated dose of interleukin-2 was 1×10(6) IU per square meter. The highest dose level induced unacceptable constitutional symptoms. Of the 23 patients who could be evaluated for response, 12 had major responses involving multiple sites. The numbers of CD4+ Treg cells were preferentially increased in all patients, with a peak median value, at 4 weeks, that was more than eight times the baseline value (P<0.001), without affecting CD4+ conventional T (Tcon) cells. The Treg:Tcon ratio increased to a median of more than five times the baseline value (P<0.001). The Treg cell count and Treg:Tcon ratio remained elevated at 8 weeks (P<0.001 for both comparisons with baseline values), then declined when the patients were not receiving interleukin-2. The increased numbers of Treg cells expressed the transcription factor forkhead box P3 (FOXP3) and could inhibit autologous Tcon cells. Immunologic and clinical responses were sustained in patients who received interleukin-2 for an extended period, permitting the glucocorticoid dose to be tapered by a mean of 60% (range, 25 to 100). CONCLUSIONS: Daily low-dose interleukin-2 was safely administered in patients with active chronic GVHD that was refractory to glucocorticoid therapy. Administration was associated with preferential, sustained Treg cell expansion in vivo and amelioration of the manifestations of chronic GVHD in a substantial proportion of patients. (Funded by a Dana-Farber Dunkin' Donuts Rising Star award and others; ClinicalTrials.gov number, NCT00529035.).

DOI： 10.1056/NEJMoa1108188

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) play an important role in the control of chronic graft-versus-host disease (cGVHD). In this study, we examined telomere length and telomerase activity of Treg and conventional CD4(+) T cells (Tcon) in 61 patients who survived more than 2 years after allogeneic hematopoietic stem cell transplantation. Cell proliferation and expression of Bcl-2 were also measured in each subset. Treg telomere length was shorter and Treg telomerase activity was increased compared with Tcon (P < .0001). After transplantation, Treg were also more highly proliferative than Tcon (P < .0001). Treg number, telomerase activity, and expression of Bcl-2 were each inversely associated with severity of cGVHD. These data indicate that activation of telomerase is not sufficient to prevent telomere shortening in highly proliferative Treg. However, telomerase activation is associated with increased Bcl-2 expression and higher Treg numbers in patients with no or mild cGVHD. In contrast, patients with moderate or severe cGVHD have fewer Treg with lower levels of telomerase activity and Bcl-2 expression. These results suggest that failure to activate Treg telomerase may restrict proliferative capacity and increase apoptotic susceptibility, resulting in the loss of peripheral tolerance and the development of cGVHD.

DOI： 10.1182/blood-2011-06-362137

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

CD4+CD25+Foxp3+ Tregs have an indispensable role in the maintenance of tolerance after allogeneic HSC transplantation (HSCT). Patients with chronic graft-versus-host disease (GVHD) have fewer circulating Tregs, but the mechanisms that lead to this deficiency of Tregs after HSCT are not known. Here, we analyzed reconstitution of Tregs and conventional CD4+ T cells (Tcons) in patients who underwent allogeneic HSCT after myeloablative conditioning. Following transplant, thymic generation of naive Tregs was markedly impaired, and reconstituting Tregs had a predominantly activated/memory phenotype. In response to CD4+ lymphopenia after HSCT, Tregs underwent higher levels of proliferation than Tcons, but Tregs undergoing homeostatic proliferation also showed increased susceptibility to Fas-mediated apoptosis. Prospective monitoring of CD4+ T cell subsets revealed that Tregs rapidly expanded and achieved normal levels by 9 months after HSCT, but Treg levels subsequently declined in patients with prolonged CD4+ lymphopenia. This resulted in a relative deficiency of Tregs, which was associated with a high incidence of extensive chronic GVHD. These studies indicate that CD4+ lymphopenia is a critical factor in Treg homeostasis and that prolonged imbalance of Treg homeostasis after HSCT can result in loss of tolerance and significant clinical disease manifestations.

DOI： 10.1172/JCI41072

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We have accomplished the selective formation of rhombic dodecahedral microparticles on the submicrometer to micrometer scale by the reaction of [70]fullerene (C(70)) with primary aliphatic diamines. The morphology of the resultant microparticles was analyzed by scanning electron microscopy, powder X-ray diffraction, and other spectroscopic methods, demonstrating that the resultant particles held a rhombic dodecahedral shape having a simple cubic lattice structure and that primary aliphatic amines were mostly trapped inside the particles through electronic interaction between C(70) and amines. Furthermore, we have discovered interesting structural characteristics in which the incorporated amines could be removed from the C(70) microparticles or exchanged with other primary aliphatic diamines.

DOI： 10.1021/la903355e

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Taylor and Francis Inc.  

DOI： 10.4161/chim.1.1.11996

Scopus

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The effects of a novel salvage regimen, IDEA (ifosfamide, cytosine arabinoside, etoposide and dexamethasone), which does not include anthracycline or platinum, in patients with non-Hodgkin's lymphoma (NHL) were examined. PATIENTS AND METHODS: Thirty-four patients with refractory or relapsed NHL were treated with IDEA. RESULTS: The overall remission and complete remission rates were 67.6% and 35.3%, respectively. The toxicity of IDEA was tolerable. With a median follow-up of 14 months, one-year overall survival (OS) and progression-free survival rates were 75.1% and 43.7%, respectively. Adequate numbers of CD34(+) cells were obtained in 77.8% of the patients assigned to receive autologous peripheral blood stem cell (PBSC) transplantation. High-dose chemotherapy with autologous PBSC transplantation was carried out in 14 patients; their 3-year OS was 75.0%, with a median follow-up of 38 months. CONCLUSION: IDEA is an effective second-line chemotherapy regimen for NHL patients and has an excellent PBSC-mobilizing effect.

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Dendritic cells (DCs) can be classified into 2 distinct subsets: conventional DCs (cDCs) and plasmacytoid DCs (pDCs). cDCs can prime antigen-specific T-cell immunity, whereas in vivo function of pDCs as antigen-presenting cells remains controversial. We evaluated the contribution of pDCs to allogeneic T-cell responses in vivo in mouse models of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation by an add-back study of MHC-expressing pDCs into major histocompatibility complex-deficient mice that were resistant to GVHD. Alloantigen expression on pDCs alone was sufficient to prime alloreactive T cells and cause GVHD. An inflammatory environment created by host irradiation has the decisive role in maturing pDCs for T-cell priming but this process does not require Toll-like receptor signaling. Thus, functional outcomes of pDC-T-cell interactions depend on the immunologic context of encounter. To our knowledge, these results are the first to directly demonstrate an in vivo pathogenic role of pDCs as antigen-presenting cells in an antigen-specific T cell-mediated disease in the absence of other DC subsets and to provide important insight into developing strategies for tolerance induction in transplantation.

DOI： 10.1182/blood-2008-07-168609

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Exposure of offspring to noninherited maternal antigens (NIMAs) during pregnancy may have an impact on transplantations performed later in life. Using a mouse model, we recently showed that bone marrow transplantation (BMT) from NIMA-exposed offspring to the mother led to a reduction of graft-versus-host disease (GVHD). Since offspring can also be exposed to NIMAs by breastfeeding after birth, we tested whether breast milk could mediate the tolerogenic NIMA effect. We found that oral exposure to NIMAs by breastfeeding alone was sufficient to reduce GVHD, and that in utero exposure to NIMAs is required for maximum reduction of GVHD. The tolerogenic milk effects disappeared when donor mice were injected with CD25 monoclonal antibodies during the lactation period, suggesting a CD4(+)CD25(+) regulatory T cell-dependent mechanism. Our results suggest a previously unknown impact of breastfeeding on the outcome of transplantation.

DOI： 10.1182/blood-2008-05-155283

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A prospective randomized clinical trial assessed the efficacy and tolerance of micafungin compared with that of standard fluconazole treatment in patients undergoing hematopoietic stem cell transplantation (HSCT). Adult patients (n = 106) were randomly assigned to receive prophylaxis with either micafungin 150 mg (n = 52), or fluconazole 400 mg (n = 52). Success was defined as the absence of suspected, proven, or probable invasive fungal infection (IFI) through the end of therapy and the absence of proven or probable IFI through the end of the 4-week period following treatment. The overall efficacy of micafungin was comparable to that of fluconazole (94 vs. 88%; difference 6.0%; 95% confidence interval, -5.4 to +17.4%; P = 0.295). A total of 2 (4.0%) of 50 patients in the micafungin arm and 6 (12.0%) of 50 patients in the fluconazole arm received empirical antifungal therapy (P = 0.06). Micafungin treatment did not result in increasing adverse effects and had a safe profile as fluconazole in neutropenic patients. This randomized trial indicates that the efficacy and tolerance of micafungin 150 mg was comparable to that of fluconazole 400 mg, suggesting that micafungin at 150 mg daily represents a valuable new treatment option for antifungal prophylaxis in HSCT recipients.

DOI： 10.1007/s12185-008-0196-y

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER CHEMICAL SOC  

Porphyrin-fullerene C-60 multilayered films have been successfully fabricated on an indium-tin-oxide (ITO) substrate by step-by-step, self-assembling, and surface sol-gel processes. First, cysteamine was self-assembled on the ITO surface, and then a C-60 layer was formed via N-H addition reaction. The layered C-60 further underwent another N-H addition with 1,2-diaminoethane to enable formation of the subsequent C-60 layer, giving a double-layered C-60 film. Meanwhile, the layered C-60 was treated with 2-aminoethanol to implant hydroxy groups on the C-60 layer, which was essential to promote the surface sol-gel reaction with titanium(IV) butoxide for implanting the titanium oxide layer. Then tetracarboxyphenylporphyrin was superimposed on the titanium oxide layer by the subsequent surface sol-gel reaction. By repeating these surface sol-gel reactions, the porphyrin layer was further assembled on the outermost layer. Accordingly, the porphyrin and C-60 multilayered films could be fabricated by the series of above-described step-by-step reactions. Absorption, fluorescence, quartz crystal microbalance, and photoelectrochemical investigations were carried out. Considerable photoinduced electron transfer between photoexcited porphyrin to C-60 was verified, even in the presence of the titanium oxide linking layer. Appreciable photocurrent generation from the multilayered films was observed, and its mechanism is described.

DOI： 10.1021/jp711180m

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbmt.2007.10.023

PubMed

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：岡山医学会  

DOI： 10.4044/joma.120.23

CiNii Article

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2008&ichushi_jid=J00175&link_issn=&doc_id=20080512270004&doc_link_id=10.4044%2Fjoma.120.23&url=https%3A%2F%2Fdoi.org%2F10.4044%2Fjoma.120.23&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

掲載種別：研究論文（学術雑誌）   出版者・発行元：American Society of Hematology  

<title>Abstract</title>
The widespread application of hematopoietic stem cell transplantation (HSCT) is limited by lack of a histocompatible donor in a proportion of patients who have a rare HLA haplotype. For these patients, allogeneic HSCT from an HLA-mismatched relative donor is complicated with a high incidence of severe graft-versus-host disease (GVHD). Exposure to noninherited maternal antigens (NIMAs) during pregnancy may have an impact on transplantation later in life. We recently demonstrated in a mouse model that a “child-to-mother” BMT from a NIMA-exposed donor reduced the mortality and morbidity of GVHD, but a “mother-to-child” BMT did not reduce GVHD (Matsuoka, 2006). We therefore hypothesized that breast-feeding could play a role on the induction of the tolerogenic NIMA effect. To test this hypothesis, we generated NIMA-exposed mice by mating a B6 (H–2b) male and a B6D2F1 (H–2b/d) female to generate H–2b/b offspring. These H–2b/b offspring were then nursed by either a B6D2F1 mother (in utero and oral exposure to NIMAs) or a B6 foster mother (in utero exposure to NIMAs). Transplantation from donors exposed to NIMA in utero alone produced more severe GVHD than BMT from in utero and orally exposed donors, demonstrating that breast-feeding is required for the induction of maximum NIMA effects. Next, to examine whether breast-feeding alone could mediate NIMA effects, we generated mice exposed to NIMA orally by nursing a new born B6 mouse with a B6D2F1 foster mother. CD4+ T cells isolated from these mice were cultured with B6D2F1 stimulators. Proliferation of these cells in response to NIMAs was significantly reduced in comparison to that from the controls. Lethally irradiated B6D2F1 recipients were transplanted with 2 × 106 T cells from these mice or controls together with 5 × 106 T cell-depleted bone marrow from control donors. Five days after transplant, donor T cell expansion and production of IFN-γ were significantly reduced in recipients of orally NIMA exposed donors than controls, resulting in a significant reduction of GVHD mortality (48% vs 80%, p&amp;lt;0.05). The tolerogenic milk effects were completely abolished when lethally irradiated B6D2F1 mice were transplanted with 1 × 106 CD25-depleted CD4+ T cells from the milk-mediated NIMA-exposed mice, thus suggesting that donor CD4+ CD25+ T cells play a role in the tolerogenic milk effects. Next, we hypothesized that generation of regulatory T cells in neonates during lactation period is essential for the induction of the tolerogenic milk effects. The anti-CD25 mAbs, PC61, is capable of depleting CD25+ cells in vivo. New born B6 mice nursed by a B6D2F1 foster mother were subcutaneously injected with anti-CD25 mAbs on days 1 and 8 of life, resulting in a decrease in numbers of Foxp3+ CD4+ CD25+ cells in spleens at 3-week-old. These mice were used as BMT donors at 8-week-old when the numbers of the regulatory T cells had recovered. After BMT from these donors, reduction of GVHD was not observed. These results suggest that development of Foxp3+ CD4+ CD25+ regulatory T cells during lactation is critical for the induction of the tolerogenic milk effects. Our findings may have immediate implications for clinical BMT to use a NIMA-mismatched donor in the absence of a HLA-identical donor in HLA mismatched HSCT.

DOI： 10.1182/blood.v110.11.2165.2165

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: T cells that undergo lymphopenia-induced proliferation (LIP) are characterized by greater effector and anti-tumor function than naïve T cells. But the ability of these T cells in causing graft-versus-host disease (GVHD) is not known. METHODS: We tested the hypothesis that donor T cells that had undergone LIP would cause more severe GVHD than naïve T cells by utilizing well-characterized murine experimental models of allogeneic bone marrow transplantation (BMT). RESULTS: Contrary to our hypothesis, LIP of donor T cells under either noninflammatory or irradiated conditions caused significantly reduced GVHD as determined by survival, clinical, pathologic, and biochemical parameters than naïve T cells. Compared to naïve donor T cells, LIP T cells demonstrated reduced expansion in vivo and in vitro after allogeneic BMT. The reduction in GVHD mortality and severity was observed across multiple strains after allogeneic BMT. In vivo mechanistic studies by cell depletion demonstrated an increase in the CD44(hi) "memory" phenotype T cells and not the CD4(+)CD25(+) T cell subset to be critical for the reduction in GVHD. CONCLUSIONS: These data demonstrate that LIP of T cells regulates acute GVHD severity in contrast to their ability to cause increased allograft rejection, autoimmunity, or anti-tumor immunity.

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

FTY720 is a novel immunosuppressant that improves the outcomes after solid organ and bone marrow transplantation (BMT) due to the sequestration of T cells into LN. We tested the hypothesis that the sequestration of donor T cells in LN by FTY720 would enhance their interaction with host APC, thus causing a greater degree of activation-induced apoptosis of alloreactive T cells, and thereby resulting in a reduction of graft-vs.-host disease (GVHD). The short-term administration of FTY720 improved the recipient survival after allogeneic BMT. FTY720 treatment facilitated a rapid contraction of the donor T cell pool in association with an increased degree of apoptosis of donor T cells. The donor T cell reactivity to host alloantigens was diminished in host's LN and adoptive transfer of donor T cells isolated from LN of FTY720-treated recipients of allogeneic BMT induced less severe GVHD in secondary recipients than the transfer from controls. Caspase-dependent apoptosis was involved in this mechanism because FTY720-induced protection was abrogated when a pan-caspase inhibitor was administered. These findings thus demonstrate the presence of a novel mechanism by which FTY720 modulates the allogeneic T cell responses: namely, by the induction of activation-induced apoptosis of alloreactive T cells in LN.

PubMed

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記述言語：英語   出版者・発行元：AMER SOC HEMATOLOGY  

DOI： 10.1182/blood.V108.11.2957.2957

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We report a case of T-cell chronic lymphoproliferative disorder (CLPD) that shows neither features of T-cell prolymphocytic leukemia nor disease progression for more than 34 months. Flow cytometric analyses of the lymphocytes revealed high expression of CD4 and CD25. Up-regulation of Foxp3, a master regulatory gene for developmental differentiation of regulatory T cells (Treg), was confirmed at mRNA and protein levels. To our knowledge, this is the first case of extremely indolent CLPD with Treg phenotype.

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：INST IMMUNOLOGY & EXPERIMENTAL THERAPY  

Allogeneic hematopoietic stem cell transplantation (HSCT) is known to cure various hematological disorders; however, its widespread use is limited due to a lack of histocompatible donors. Reciprocal cell traffic between the mother and fetus during pregnancy gives rise to postpartum fetal-maternal lymphohematopoietic microchimerism, which is frequently detected in the blood or tissue of healthy individuals. Studies in clinical and experimental transplantation provide evidence that exposure to non-inherited maternal antigens (NIMAs) during pregnancy may result in long-lasting fetomaternal microchimerism and tolerance induction. Studies of HLA-mismatched HSCT have suggested a relatively lower incidence of severe graft-versus-host disease (GVHD) after transplantation from a NIMA-mismatched donor. Studies using a mouse model have also demonstrated a "child-to-mother" bone marrow transplantation from an NIMA-exposed donor to reduce the morbidity and mortality of GVHD in an antigen-specific manner while preserving the graft-versus-leukemia effects and favoring the immune reconstitution, thus resulting in a marked improvement in outcome after HSCT. Prospective clinical studies are therefore warranted to confirm these beneficial effects of fetal-maternal tolerance in allogeneic HSCT.

DOI： 10.1007/s00005-006-0018-y

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担当区分：筆頭著者,　責任著者   記述言語：日本語  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The lack of donor availability is a major limitation to the widespread use of allogeneic hematopoietic stem cell transplantation, and therefore it would be beneficial to identify less immunogenic HLA mismatches. The maternal and fetal antigens that are transmitted through the bidirectional transplacental passage during pregnancy may induce tolerance to noninherited maternal antigens (NIMAs) in offspring and to inherited paternal antigens (IPAs) in the mother. Using mouse models of bone marrow transplantation (BMT), we found that a "child-to-mother" BMT from a NIMA-exposed donor reduced the morbidity and mortality of graft-versus-host disease in an antigen-specific manner; however, a "mother-to-child" BMT from an IPA-exposed donor did not. The NIMA-complementary BMT preserved the graft-versus-leukemia effects and favored the immune reconstitution, thus resulting in a marked improvement of the outcome after BMT. These tolerogenic NIMA effects were completely abolished by the depletion of CD4+ CD25+ cells from the donor inocula, thus suggesting the involvement of CD4+ CD25+ regulatory T cells in the tolerogenic NIMA effects. Our findings may therefore have profound implications on the performance of clinical BMT while also potentially helping to develop new strategies for using a NIMA-mismatched donor in the absence of an HLA-identical donor.

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Reciprocal cell traffic between mother and fetus during pregnancy gives rise to postpartum fetal-maternal lymphohematopoietic microchimerism, which is frequently detected in blood or tissue from healthy individuals. Although such microchimerism has been implicated in the pathogenesis of autoimmune diseases and tissue repair, recent clinical experiences have suggested the association of microchimerism with acquired immunologic hyporesponsiveness to non-inherited maternal HLA antigens (NIMAs) or inherited paternal HLA antigens (IPAs); T cell-replete HLA-haploidentical hematopoietic stem cell transplantation from a microchimeric IPA/NIMA-mismatched donor confers relatively lower incidence of severe graft-versus-host disease. The underlying mechanisms by which fetal-maternal microchimerism contributes to IPA/NIMA-specific tolerance are still elusive, although emerging experimental evidence suggests an involvement of the central deletion of IPA/NIMA-reactive T cells, the induction of peripheral regulatory T cells, and affinity-dependent modulation of NIMA-reactive B cells.

PubMed

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

A 45-year-old female with acute myelogenous leukemia (AML-M6) received an allogeneic stem cell transplantation from an HLA-identical sibling donor in June 2002. Prophylaxis against graft-versus-host disease (GVHD) consisted of cyclosporine (CsA) and short-term methotrexate. Acute GVHD did not occur and CsA was discontinued on day 145 after transplantation. However, soon thereafter she suffered from conjunctivitis, stomatitis and liver dysfunction with hypercholesterolemia and was diagnosed as having chronic GVHD. The liver dysfunction and hypercholesterolemia failed to improve despite the administration of CsA and prednisolone. Atrovastatin was not effective and immunosuppressive therapy for two months including ursodeoxycholic acid finally improved the jaundice and hypercholesterolemia. Although lipid metabolism analysis in this case disclosed the same findings as in other intrahepatic cholestatic liver diseases, the results show that the improvement of hypercholesterolemia in chronic GVHD needs the same treatment as chronic GVHD.

PubMed

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER SOC HEMATOLOGY  

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DOI： 10.1182/blood-2021-144689

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記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

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記述言語：英語   出版者・発行元：WILEY  

DOI： 10.1111/trf.15872

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記述言語：日本語   出版者・発行元：日本消化器病学会-中国支部  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER SOC HEMATOLOGY  

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DOI： 10.1182/blood-2018-99-112365

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER SOC HEMATOLOGY  

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DOI： 10.1182/blood-2018-99-111175

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記述言語：英語   出版者・発行元：(一社)日本血液学会-東京事務局  

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記述言語：英語   出版者・発行元：(一社)日本血液学会-東京事務局  

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記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

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記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

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記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ELSEVIER SCIENCE INC  

DOI： 10.1016/j.bbmt.2017.12.382

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER SOC HEMATOLOGY  

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記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

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記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER SOC HEMATOLOGY  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER SOC HEMATOLOGY  

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記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ELSEVIER SCIENCE INC  

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記述言語：英語   出版者・発行元：(一社)日本リンパ網内系学会  

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記述言語：日本語   出版者・発行元：(一社)日本リンパ網内系学会  

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記述言語：日本語   出版者・発行元：(一社)日本リンパ網内系学会  

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記述言語：日本語   出版者・発行元：(一社)日本リンパ網内系学会  

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記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

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記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

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記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

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記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER SOC HEMATOLOGY  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER SOC HEMATOLOGY  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER SOC HEMATOLOGY  

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その他リンク： http://search.jamas.or.jp/link/ui/2015087067

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記述言語：日本語   出版者・発行元：(一社)日本癌治療学会  

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