研究者詳細 - 宮原　信明

46 COPDおよびCOPD合併喘息モデルに対するロイコトリエン受容体拮抗薬の効果について(動物モデル3,第58回日本アレルギー学会秋季学術大会)

池田元洋, 金廣有彦, 宮原信明, 早稲田公一, 古賀光, 渊本康子, 近藤稔人, 小野勝一郎, 平野淳, 谷本安, 片岡幹男, 谷本光音

アレルギー 57 ( 9 ) 1458 - 1458 2008年

MS17-10 肺サルコイドーシス治療におけるメソトレキサート(MTX)の有用性に関する検討(膠原病と類縁疾患,第58回日本アレルギー学会秋季学術大会)

谷本安, 中田安成, 片岡幹男, 早稲田公一, 池田元洋, 渊本康子, 古賀光, 市川裕久, 宮原信明, 金廣有彦, 森由弘, 谷本光音

アレルギー 57 ( 9 ) 1436 - 1436 2008年

MS9-7 アレルギー性気道炎症におけるCCR5の役割について(基礎-サイトカイン/ケモカイン,第58回日本アレルギー学会秋季学術大会)

渊本康子, 金廣有彦, 宮原信明, 古賀光, 池田元洋, 早稲田公一, 谷本安, 片岡幹男, 谷本光音, 松島綱治

アレルギー 57 ( 9 ) 1413 - 1413 2008年

MS2-2 高齢者喘息の管理における喘息コントロールテスト(ACT)の有用性に関する検討(気管支喘息コントロールの評価,第20回日本アレルギー学会春季臨床大会)

谷本安, 渊本康子, 尾形佳子, 早稲田公一, 金澤聰, 宮原信明, 金廣有彦, 片岡幹男, 高橋清, 谷本光音

アレルギー 57 ( 3 ) 358 - 358 2008年

P236 喘息患者指導における医師,薬剤師の連携に関する調査研究(気管支喘息治療3,第20回日本アレルギー学会春季臨床大会)

岡田千春, 平野淳, 木村五郎, 谷本安, 金廣有彦, 宮原信明, 宗田良, 高橋清

アレルギー 57 ( 3 ) 439 - 439 2008年

P108 モンテルカストが有効であった高齢者好酸球性胃腸炎の1例(好酸球1,第20回日本アレルギー学会春季臨床大会)

平野淳, 岡田千春, 木村五郎, 谷本安, 金廣有彦, 宮原信明, 片岡幹男, 宗田良, 高橋清

アレルギー 57 ( 3 ) 407 - 407 2008年

[Coinfection with Mycoplasma pneumoniae and Chlamydophila pneumoniae in a middle-aged adult]. 査読

Kubo T, Takigawa N, Tanimoto Y, Ichihara E, Tabata M, Miyahara N, Kanehiro A, Kiura K, Tanimoto M

Nihon Kokyuki Gakkai zasshi = the journal of the Japanese Respiratory Society 45 ( 10 ) 808 - 811 2007年10月

CD8(+) T cell-mediated airway hyperresponsiveness and inflammation is dependent on CD4(+)IL-4(+) T cells 査読

Toshiyuki Koya, Nobuaki Miyahara, Katsuyuki Takeda, Shigeki Matsubara, Hiroyuki Matsuda, Christina Swasey, Annette Balhorn, Azzeddine Dakhama, Erwin W. Gelfand

JOURNAL OF IMMUNOLOGY 179 ( 5 ) 2787 - 2796 2007年9月

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 ASSOC IMMUNOLOGISTS

CD4(+) T cells, particularly Th2 cells, play a pivotal role in allergic airway inflammation. However, the requirements for interactions between CD4+ and CD8(+) T cells in airway allergic inflammation have not been delineated. Sensitized and challenged OT-1 mice in which CD8(+) T cells expressing the transgene for the OVA(257-264) peptide (SIINFEKL) failed to develop airway hyperresponsiveness (AHR), airway eosinophilia, Th2 cytokine elevation, or goblet cell metaplasia. OT-1 mice that received naive CD4(+)IL-4(+) T cells but not CD4(+)IL-4(-) T cells before sensitization developed all of these responses to the same degree as wild-type mice. Moreover, recipients of CD4(+)IL-4(+) T cells developed significant increases in the number of CD8(+)IL-13(+) T cells in the lung, whereas sensitized OT-1 mice that received primed CD4(+) T cells just before challenge failed to develop these responses. Sensitized CD8-deficient mice that received CD8(+) T cells from OT-1 mice that received naive CD4(+) T cells before sensitization increased AHR and eosinophil numbers in bronchoalveolar lavage fluid when challenged with allergen. In contrast, sensitized CD8-deficient mice receiving CD8(+) T cells from OT-1 mice without CD4(+) T cells developed reduced AHR and eosinophil numbers in bronchoalveolar lavage fluid when challenged. These data suggest that interactions between CD4(+) and CD8(+) T cells, in part through IL-4 during the sensitization phase, are essential to the development of CD8(+)IL-13(+) T cell-dependent AHR and airway allergic inflammation.

DOI： 10.4049/jimmunol.179.5.2787

Activation of naturally occurring lung CD4(+) CD25(+) regulatory T cells requires CD8 and MHC I interaction 査読

Anthony Joetham, Katsuyuki Takeda, Nobuaki Miyahara, Shigeki Matsubara, Hiroshi Ohnishi, Toshiyuki Koya, Azzeddine Dakhama, Erwin W. Gelfand

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 104 ( 38 ) 15057 - 15062 2007年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATL ACAD SCIENCES

Naturally occurring Foxp3(+)CD4(+)CD25(+) T cells (nTregs) isolated from lungs of naive mice regulate allergic airway hyperresponsiveness (AHR) and inflammation. Here, we demonstrate the critical requirement for engagement of MHC class I on CD4(+)CD25(+) T cells by CD8 for the functional activation of these nTregs. Suppression of allergen-induced AHR and inflammation by nTregs was abolished in mice treated with anti-CD8. Correspondingly, decreased levels of IL-10 and TGF-beta and increased levels of Th2 cytokines in bronchoalveolar lavage were detected in these treated mice. Similarly, nTregs isolated from beta 2m(-/-) mice or from mice treated with anti-MHC I antibody in vitro before intratracheal transfer failed to modulate AHR or inflammation. Coculture of nTregs with CD8(+) T cells increased IL-10 and TGF-beta. Addition of anti-MHC I or anti-CD8 reduced IL-10 and TGF-beta. These results demonstrate that functional activation of nTregs requires the interaction between MHC I on CD4(+)CD25(+) T cells and CD8.

DOI： 10.1073/pnas.0706765104

Airway hyperresponsiveness through synergy of gamma delta T cells and NKT cells 査読

Niyun Jin, Nobuaki Miyahara, Christina L. Roark, Jena D. French, M. Kemal Aydintug, Jennifer L. Matsuda, Laurent Gapin, Rebecca L. O'Brien, Erwin W. Gelfand, Willi K. Born

JOURNAL OF IMMUNOLOGY 179 ( 5 ) 2961 - 2968 2007年9月

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 ASSOC IMMUNOLOGISTS

Mice sensitized and challenged with OVA were used to investigate the role of innate T cells in the development of allergic airway hyperresponsiveness (AHR). AHR, but not eosinophilic airway inflammation, was induced in T cell-deficient mice by small numbers of cotransferred gamma(delta) T cells and invariant NKT cells, whereas either cell type alone was not effective. Only V gamma 1(+)V delta 5(+) gamma delta T cells enhanced AHR. Surprisingly, OVA-specific alpha beta T cells were not required, revealing a pathway of AHR development mediated entirely by innate T cells. The data suggest that lymphocytic synergism, which is key to the Ag-specific adaptive immune response, is also intrinsic to T cell-dependent innate responses.

DOI： 10.4049/jimmunol.179.5.2961

Arhgef1 is required by T cells for the development of airway hyperreactivity and inflammation 査読

Jeanette P. Brown, Christian Taube, Nobuaki Miyahara, Toshiyuki Koya, Roberta Pelanda, Erwin W. Gelfand, Raul M. Torres

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 176 ( 1 ) 10 - 19 2007年7月

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 THORACIC SOC

Rationale: Arhgef1 is an intracellular protein, expressed by hematopoietic cells, that regulates signaling by both G protein-coupled receptors and RhoA, and, consequently, is required for appropriate migration and adhesion of diverse leukocyte populations. Objectives: To evaluate a possible contribution for Arhgef1 in the development of airway inflammation and airway hyperreactivity. Methods: Arhgef1-deficient (Arhgef1(-/-)) and wild-type (WT) mice were sensitized and airway challenged, followed by measurement of airway responsiveness to inhaled methacholine. Inflammation was assessed by several parameters that included flow cytometric analysis and histology. Arhgef1-deficient recipients were reconstituted with WT T lymphocytes before sensitization and challenge, and again measured for airway responsiveness and inflammation. Cytokine production in response to specific antigen was measured in cultures of isolated leukocytes from lung and spleen and compared with the levels generated in lung and spleen explant cultures. Measurements and Main Results: Arhgef1(-/-) mice display significantly reduced airway hyperreactivity, Th2 cytokine production, and lung inflammation, despite intact systemic immunity. After airway challenge of Arhgef1(-/-) mice, antigen-specific T cells were present in mutant lungs, but were found to interact with CD11c(+) cells at a significantly reduced frequency. Adoptive transfer of WTTcells into Arhgef1(-/-) mice restored airway hyperreactivity and inflammation. Conclusions: These data demonstrate that T cells depend on Arhgef1 to promote lung inflammation. Moreover, a deficiency in Arhgef1 results in reduced T cell-CD11c(+) antigen-presenting cell interaction, and likely underscores the inability of Arhgef1(-/-) mice to mount an adaptive immune response to airway challenge.

DOI： 10.1164/rccm.200702-270OC

IL-10-treated dendritic cells decrease airway hyperresponsiveness and airway inflammation in mice 査読

Toshiyuki Koya, Hiroyuki Matsuda, Katsuyuki Takeda, Shigeki Matsubara, Nobuaki Miyahara, Annette Balhorn, Azzeddine Dakhama, Erwin W. Gelfand

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 119 ( 5 ) 1241 - 1250 2007年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MOSBY-ELSEVIER

Background: IL-10 affects dendritic cell (DC) function, but the effects on airway hyperresponsiveness (AHR) and inflammation are not defined.
Objective: We sought to determine the importance of IL-10 in regulating DC function in allergen-induced AHR and airway inflammation.
Methods: DCs were generated from bone marrow in the presence or absence of IL-10. In vivo IL-10-treated DCs from IL-10(+/+) and IL-10(-/-) donors pulsed with ovalbumin (OVA) were transferred to naive or sensitized mice before challenge. In recipient mice AHR, cytokine levels, cell composition of bronchoalveolar lavage (BAL) fluid, and lung histology were monitored.
Results: In vitro, IL-10-treated DCs expressed lower levels of CD11c, CD80, and CD86; expressed lower levels of IL-12; and suppressed T(H)2 cytokine production. In vivo, after transfer of OVA-pulsed IL-10-treated DCs, naive mice did not have AHR, airway eosinophilia, T(H)2 cytokine increase in BAL fluid, or goblet cell metaplasia when challenged, and in sensitized and challenged mice IL-10-treated I)Cs suppressed these responses. Levels of IL-10 in BAL fluid and numbers of lung CD4(+)IL-10(+) T cells were increased in mice that received OVA-pulsed IL-10-treated DCs. Transfer of IL-10-treated DCs from IL-10-deficient mice were ineffective in suppressing the responses in sensitized and challenged mice.
Conclusions: These data demonstrate that IL-10-treated DCs are potent suppressors of the development of AHR, inflammation, and T(H)2 cytokine production; these regulatory functions are at least in part through the induction of endogenous (DQ production of IL-10. Clinical implications: Modification of DC function by IL-10 can attenuate lung allergic responses, including the development of AHR.

DOI： 10.1016/j.jaci.2007.01.039

IL-2 and IL-18 attenuation of airway hyperresponsiveness requires STAT4, IFN-gamma, and natural killer cells 査読

Shigeki Matsubara, Katsuyuki Takeda, Taku Kodama, Anthony Joetham, Nobuaki Miyahara, Toshiyuki Koya, Christina H. Swasey, Masakazu Okamoto, Azzeddine Dakhama, Erwin W. Gelfand

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY 36 ( 3 ) 324 - 332 2007年3月

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 THORACIC SOC

IL-18 is known to induce IFN-gamma production, which is enhanced when combined with IL-2. In the present study, we investigated whether the combination of exogenous IL-2 and IL-18 alters airway hyperresponsiveness (AHR) and airway inflammation. Sensitized mice exposed to ovalbumin (OVA) challenge developed AHR, inflammatory cells in the bronchoalveolar lavage (BAL) fluid, and increases in levels of Th2 cytokines and goblet cell numbers. The combination of IL-2 and IL-18, but neither alone, prevented these changes while increasing levels of IL-12 and IFN-gamma. The combination of IL-2 and IL-18 was ineffective in IFN-gamma-deficient and signal transducer and activator of transcription (STAT)4-deficient mice. Flow cytometry analysis showed significant increases in numbers of IFN-gamma-positive natural killer (NK) cells in the lung after treatment with the combination therapy, and transfer of lung NK cells isolated from sensitized and challenged mice treated with the combination significantly suppressed AHR and BAL eosinophilia. These data demonstrate that the combination of IL-2 and IL-18 prevents AHR and airway inflammation, likely through IL-12-mediated induction of IFN-gamma production in NK cells.

DOI： 10.1165/rcmb.2006-0231OC

Naturally occurring lung CD4(+) CD25(+) T cell regulation of airway allergic responses depends on IL-10 induction of TGF-beta 査読

Anthony Joetham, Katsuyuki Takada, Christian Taube, Nobuaki Miyahara, Satoko Matsubara, Toshiyuki Koya, Yeong-Ho Rha, Azzeddine Dakhama, Erwin W. Gelfand

JOURNAL OF IMMUNOLOGY 178 ( 3 ) 1433 - 1442 2007年2月

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 ASSOC IMMUNOLOGISTS

Peripheral tolerance to allergens is mediated in large part by the naturally occurring lung CD4(+)CD25(+) T cells, but their effects on allergen-induced airway responsiveness have not been well defined. Intratracheal, but not i.v., administration of naive lung CD4(+)CD25(+) T cells before allergen challenge of sensitized mice, similar to the administration of the combination of rIL-10 and rTGF-beta, resulted in reduced airway hyperresponsiveness (AHR) and inflammation, lower levels of Th2 cytokines, higher levels of IL-10 and TGF-beta, and less severe lung histopathology. Significantly, CD4(+)CD25(+) T cells isolated from IL-10(-/-) mice had no effect on AHR and inflammation, but when incubated with rIL-10 before transfer, suppressed AHR, and inflammation, and was associated with elevated levels of bronchoalveolar lavage TGF-beta levels. By analogy, anti-TGF-beta treatment reduced regulatory T cell activity. These data identify naturally occurring lung CD4(+)CD25(+) T cells as capable of regulating lung allergic responses in an IL-10- and TGF-beta-dependent manner.

DOI： 10.4049/jimmunol.178.3.1433

Critical role of the Fc receptor gamma-chain on APCs in the development of allergen-induced airway hyperresponsiveness and inflammation 査読

Kenichi Kitamura, Katsuyuki Takeda, Toshiyuki Koya, Nobuaki Miyahara, Taku Kodama, Azzeddine Dakhama, Toshiyuki Takai, Atsushi Hirano, Mitsune Tanimoto, Mine Harada, Erwin W. Gelfand

JOURNAL OF IMMUNOLOGY 178 ( 1 ) 480 - 488 2007年1月

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 ASSOC IMMUNOLOGISTS

The FeR common y-chain (FcRy) is an essential component of the receptors Fe epsilon RI, Fc gamma RI, and Fc gamma RIII, which are expressed on many inflammatory cell types. The role of these receptors in the initiation or maintenance of allergic inflammation has not been well defined. FcR gamma-deficient (FcRy(-/-)) and control (wild-type (WT)), mice were sensitized and subsequently challenged with OVA. Following sensitization and challenge to OVA, FeRy-deficient (FcRy(-/-)) mice developed comparable levels of IgE and IgG1 as WT mice. However, numbers of eosinophils, levels of IL-5, IL-13, and eotaxin in bronchoalveolar lavage fluid, and mononuclear cell (MNC) proliferative responses to OVA were significantly reduced, as was airway hyperresponsiveness (AHR) to inhaled methacholine. Reconstitution of FeRy(-/-) mice with whole spleen MNC from WT mice before sensitization restored development of AHR and the numbers of eosinophils in bronchoalveolar lavage fluid; reconstitution after sensitization but before OVA challenge only partially restored these responses. These responses were also restored when FcRy(-/-) mice received T cell-depleted MNC, T and B cell-depleted MNC, or bone marrow-derived dendritic cells before sensitization from FcR(+/+) or Fe gamma RIII-deficient but not FcRy(-/-) mice. The expression levels of Fc gamma RIV on bone marrow-derived dendritic cells from FcR(+/+) mice were found to be low. These results demonstrate that expression of FcR gamma, most likely Fc gamma RI, on APCs is important during the sensitization phase for the development of allergic airway inflammation and AHR.

DOI： 10.4049/jimmunol.178.1.480

IL-13 is essential to the late-phase response in allergic rhinitis 査読

Satoko Miyahara, Nobuaki Miyahara, Shigeki Matsubara, Katsuyuki Takeda, Toshiyuki Koya, Erwin W. Gelfand

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 118 ( 5 ) 1110 - 1116 2006年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MOSBY-ELSEVIER

Background: The pathophysiology of the early- and late-phase nasal response to allergen challenge is not completely defined. Recent technical advances enable direct monitoring of these responses in mice.
Objective: IL-13 is detected in the nasal membranes of both human beings and mice with allergic rhinitis, but its role in disease pathogenesis is unclear. We measured early and late nasal allergic responses after treatment with soluble IL-13R alpha 2-IgG fusion protein (sIL-13R alpha 2-Fc), and in IL-13-deficient mice (IL-13(-/-)).
Methods: IL-13(-/-) mice (BALB/c background) and wild-type mice were sensitized to ovalbumin by intraperitoneal injection and then challenged intranasally with ovalbumin without sedation. The sIL-13R alpha 2-Fc or control human IgG was administered by intraperitoneal (i.p.) injection 24 hours and 1 hour before each ovalbumin challenge. Early nasal responses after the 4th ovalbumin challenge and late nasal responses 24 hours after the 6th ovalbumin challenge were assessed. Results: Sensitized/challenged wild-type mice treated with sIL-13R alpha 2-Fc or IL-13(-/-) mice demonstrated significantly reduced late nasal responses in face of persistent nasal tissue eosinophilia; the early nasal response was little affected by targeting IL-13. Goblet cell hyperplasia was not detected in nasal membranes.
Conclusion: The data indicate that IL-13 is a major contributor to the development of a late nasal response with little influence on the early response, and without affecting nasal eosinophilic inflammation. Inhibition of IL-13 may have an important therapeutic application in preventing the persistent nasal blockage in allergic rhinitis.
Clinical implications: Current therapies for allergic rhinitis may not take into account the important differences in the pathophysiology of the early and late responses and the important role of IL-13 in sustaining chronic nasal congestion and obstruction.

DOI： 10.1016/j.jaci.2006.06.014

RANTES (CCL5) regulates airway responsiveness after repeated allergen challenge 査読

Toshiyuki Koya, Katsuyuki Takeda, Taku Kodama, Nobuaki Miyahara, Shigeki Matsubara, Annette Balhorn, Anthony Joetham, Azzedine Dakhama, Erwin W. Gelfand

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY 35 ( 2 ) 147 - 154 2006年8月

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 THORACIC SOC

RANTES (CC chemokine ligand 5) contributes to airway inflammation through accumulation of eosinophils, but the exact role of RANTES (CCL5) is not defined. C57BL/6 mice, sensitized by injection of ovalbumin (OVA) on Days I and 14, were challenged with OVA on Days 28, 29, and 30 (3 challenges, short-term-challenge model) or on Days 28, 29, 30, 36, 40, 44, and 48 (7 challenges, repeated-challenge model) and evaluated 48 h later. Anti-mouse RANTES was given intravenously, and recombinant mouse RANTES or PBS was given intratracheally. These reagents were given on Days 28, 29, and 30 in the short-term-challenge study and on Days 44 and 48 in the repeated-challenge study. After short-term challenge, there were no effects after administration of anti-RANTES or RANTES. In the repeated-challenge study, although control mice showed a decrease in airway hyperresponsiveness, administration of anti-RANTES sustained and enhanced airway hyperresponsiveness and increased goblet cell numbers. In contrast, administration of RANTES normalized airway function but reduced goblet cell numbers. IL-12 and IFN-gamma levels in BAL decreased in the anti-RANTES group and increased in the RANTES group. IFN-gamma-producing CD4 T cells in lung, and IFN-gamma production from lung T cells in response to OVA in the anti-RANTES group, were significantly decreased but were increased in the RANTES group. Anti-IFN-gamma administered with RANTES, decreased the effects of RANTES on AHR after repeated challenge. These data indicate that RANTES plays a role in the regulation of airway function after repeated allergen challenge, in part through modulation of levels of IFN-gamma and IL-12.

DOI： 10.1165/rcmb.2005-0394OC