研究者詳細 - 宮原　信明

Leukotriene B4 Release from Mast Cells in IgE-Mediated Airway Hyperresponsiveness and Inflammation 査読

Nobuaki Miyahara, Hiroshi Ohnishi, Satoko Miyahara, Katsuyuki Takeda, Shigeki Matsubara, Hiroyuki Matsuda, Masakazu Okamoto, Joan E. Loader, Anthony Joetham, Mitsune Tanimoto, Azzeddine Dakhama, Erwin W. Gelfand

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY 40 ( 6 ) 672 - 682 2009年6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

Previous studies have shown that leukotriene B4 (LTB4), a proinflammatory lipid mediator, is linked to the development of airway hyperresponsiveness through the accumulation of IL-13-producing CD8+ T cells, which express a high affinity receptor for LTB4, BLT1 (Miyahara et al., Am J Respir Crit Care Med 2005;172:161-167; J Immunol 2005;174:4979-4984). By using leukotriene A4 hydrolase-deficient (LTA4H-/-) mice, which fail to synthesize LTB4, we determined the role of this lipid mediator in allergen-induced airway responses. Two approaches were used. In the first, LTA4H-/- mice and wild-type (LTA4H+/+) mice were systemically sensitized and challenged via the airways to ovalbumin. In the second, mice were passively sensitized with anti-ovalbumin IgE and exposed to ovalbumin via the airways. Mast cells were generated from bone marrow of LTA4H+/+ mice or LTA4H-/- mice. After active sensitization and challenge, LTA4H-/- mice showed significantly lower airway hyperresponsiveness compared with LTA4H+/+ mice, and eosinophil numbers and IL-13 levels in the bronchoalveoloar lavage, of LTA4H-/- mice were also significantly lower. LTA4H-/- mice also showed decreased airway reactivity after passive sensitization and challenge. After LTA4H+/+ mast cell transfer, LTA4H-/- mice showed increased airway reactivity after passive sensitization and challenge, but not after systemic sensitization and challenge. These data confirm the important role for LTB4 in the development of altered airway responses and suggest that LTB4 secretion from mast cells is critical to eliciting increased airway reactivity after passive sensitization with allergen-specific IgE.

DOI： 10.1165/rcmb.2008-0095OC

慢性閉塞性肺疾患(COPD)を合併した進行肺非小細胞癌(NSCLC)の予後

原田大二郎, 瀧川奈義夫, 木浦勝行, 谷本安, 堀田勝幸, 平木章夫, 宮原信明, 田端雅弘, 金廣有彦, 谷本光音

日本呼吸器学会雑誌 47 ( 増刊 ) 300 - 300 2009年5月

乳癌に対する放射線照射後に発症したBOOP症候群の臨床的検討

谷本安, 久山彰一, 高尾和志, 岸俊行, 堀田勝幸, 瀧川奈義夫, 宮原信明, 金廣有彦, 田端雅弘, 木浦勝行, 片岡幹男, 谷本光音

日本呼吸器学会雑誌 47 ( 増刊 ) 325 - 325 2009年5月

Allergic Airway Hyperresponsiveness-Enhancing gamma delta T Cells Develop in Normal Untreated Mice and Fail to Produce IL-4/13, Unlike Th2 and NKT Cells 査読

Niyun Jin, Christina L. Roark, Nobuaki Miyahara, Christian Taube, M. Kemal Aydintug, J. M. Wands, Yafei Huang, Youn-Soo Hahn, Erwin W. Gelfand, Rebecca L. O'Brien, Willi K. Born

JOURNAL OF IMMUNOLOGY 182 ( 4 ) 2002 - 2010 2009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

Allergic airway hyperresponsiveness (AHR) in OVA-sensitized and challenged mice, mediated by allergen-specific Th2 cells and Th2-like invariant NKT (iNKT) cells, develops under the influence of enhancing and inhibitory gamma delta T cells. The AHR-enhancing cells belong to the V gamma 1(+) gamma delta T cell subset, cells that are capable of increasing IL-5 and IL-13 levels in the airways in a manner like Th2 cells. They also synergize with iNKT cells in mediating AHR. However, unlike Th2 cells, the AHR enhancers arise in untreated mice, and we show here that they exhibit their functional bias already as thymocytes, at an HSA(high) maturational stage. In further contrast to Th2 cells and also unlike iNKT cells, they could not be stimulated to produce IL-4 and IL-13, consistent with their synergistic dependence on iNKT cells in mediating AHR. Mice deficient in IFN-gamma, TNFRp75, or IL-4 did not produce these AHR-enhancing gamma delta T cells, but in the absence of IFN-gamma, spontaneous development of these cells was restored by adoptive transfer of IFN-gamma-competent dendritic cells from untreated donors. The i.p. injection of OVA/aluminum hydroxide restored development of the AHR enhancers in all of the mutant strains, indicating that the enhancers still can be induced when they fail to develop spontaneously, and that they themselves need not express TNFRp75, IFN-gamma, or IL-4 to exert their function. We conclude that both the development and the cytokine potential of the AHR-enhancing gamma delta T cells differs critically from that of Th2 cells and NKT cells, despite similar influences of these cell populations on AHR. The Journal of Immunology, 2009, 182: 2002-2010.

DOI： 10.4049/jimmunol.0803280

Mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2-dependent pathways are essential for CD8(+) T cell-mediated airway hyperresponsiveness and inflammation 査読

Hiroshi Ohnishi, Katsuyuki Takeda, Joanne Domenico, Joseph J. Lucas, Nobuaki Miyahara, Christina H. Swasey, Azzeddine Dakhama, Erwin W. Gelfand

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 123 ( 1 ) 249 - 257 2009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：MOSBY-ELSEVIER

Background: Ligation of the leukotriene B-4 (LTB4) receptor I on effector memory CD8(+) T cells by LTB4 is important for the recruitment of CD8(+) T cells into the airways, which appears central to the induction of airway hyperresponsiveness (AHR) and allergic inflammation. Phosphorylation of extracellular signal-regulated kinase (ERK) is important in activation and cytokine production from many cell types.
Objective: The roles of ERKs in effector CD8(+) T-cell function and on CD8(+) T cell-mediated AHR were determined.
Methods: Effector CD8(+) T cells were generated from OVA(257.264) (SIINFEKL) peptide-primed mononuclear cells from OT-1 mice. The effects of U0126, an ERK inhibitor, on effector CD8(+) T-cell function and on CD8(+) T cell-mediated AHR and allergic inflammation were examined.
Results: Pretreatment of effector CD8(+) T cells with U0126 suppressed anti-CD3/anti-CD28-induced ERK1/2 phosphorylation and cytokine production, but did not affect LTB4-induced Ca2+ mobilization or chemotaxis. Adoptive transfer of U0126-treated CD8(+) T cells into sensitized mice before secondary allergen challenge resulted in significant decreases in AHR, eosinophilic inflammation, goblet cell metaplasia, and IL-5 and IL-13 levels in bronchoalveolar lavage fluid of recipient mice. The number of transferred CD8(+) T cells accumulating in bronchoalveolar lavage fluid or lungs was unaffected by treatment.
Conclusion: ERK1/2-dependent pathways are essential for the effector functions of CD8(+) T cells, including T(H)2 cytokine production, allergic inflammation, and development of AHR. Inhibition of ERK1/2 signaling has potential therapeutic benefit in preventing CD8(+) T cell-mediated AHR. (J Allergy Clin Immunol 2009;123:249-57.)

DOI： 10.1016/j.jaci.2008.10.054

PO8-3 血液悪性腫瘍の治療中に出現した胸部異常影に対する気管支鏡検査(びまん性疾患,ポスター8,第32回日本呼吸器内視鏡学会学術集会)

村上斗司, 瀧川奈義夫, 谷本安, 二宮崇, 栗本悦子, 能島大輔, 本多宣裕, 堀田勝幸, 宮原信明, 田端雅弘, 金廣有彦, 木浦勝行, 谷本光音

気管支学 31 S157 2009年

PO11-1 非乾酪性類上皮細胞肉芽腫病変を伴ったために診断に苦慮したホジキンリンパ腫の1例(リンパ腫・胸腺・胸膜腫瘍,ポスター11,第32回日本呼吸器内視鏡学会学術集会)

栗本悦子, 谷本安, 瀧川奈義夫, 二宮崇, 能島大輔, 村上斗司, 本多宣裕, 堀田勝幸, 宮原信明, 田端雅弘, 金廣有彦, 木浦勝行, 谷本光音, 片岡幹男

気管支学 31 S165 2009年

41.気管支鏡下生検で診断された19年後の再発乳癌の1例(第17回日本呼吸器内視鏡学会中国四国支部会)

村上斗司, 木浦勝行, 瀧川奈義夫, 能島大輔, 本多宣裕, 二宮崇, 栗本悦子, 堀田勝幸, 宮原信明, 谷本安, 田端雅弘, 金廣有彦, 谷本光音

気管支学 31 ( 3 ) 178 - 178 2009年

MS40-7 乳癌に対する放射線照射後に発症したBOOP症候群の治療・管理に関する検討(食物アレルギー・薬物アレルギー-病態生理と治療5-薬物アレルギー-,第59回日本アレルギー学会秋季学術大会)

谷本安, 高尾和志, 能島大輔, 早稲田公一, 宮原信明, 金廣有彦, 片岡幹男, 中田安成, 谷本光音

アレルギー 58 ( 8 ) 1328 - 1328 2009年

MS17-#2 STAT6欠損慢性喘息モデルにおける気道過敏性,気道炎症,気道リモデリング形成についての検討(気管支喘息-動物モデル2,第59回日本アレルギー学会秋季学術大会)

小野勝一郎, 金廣有彦, 宮原信明, 平野淳, 池田元洋, 古賀光, 渕本康子, 早稲田公一, 能島大輔, 栗本悦子, 谷本安, 片岡幹男, 伊藤亘, 谷本光音

アレルギー 58 ( 8 ) 1250 - 1250 2009年

MS16-12 既にアレルギー性気道炎症を発症したマウスモデルにおけるロイコトリエンB4の役割(気管支喘息-動物モデル1,第59回日本アレルギー学会秋季学術大会)

早稲田公一, 宮原信明, 金廣有彦, 池田元洋, 古賀光, 渕本康子, 栗本悦子, 能島大輔, 谷本安, 片岡幹男, Gelfand Erwin, 谷本光音

アレルギー 58 ( 8 ) 1250 - 1250 2009年

Leukotriene B(4) receptor 1 expression on dendritic cells is required for the development of Th2 responses and allergen-induced airway hyperresponsiveness 査読

Nobuaki Miyahara, Hiroshi Ohnishi, Hiroyuki Matsuda, Satoko Miyahara, Katsuyuki Takeda, Toshiyuki Koya, Shigeki Matsubara, Masakazu Okamoto, Azzeddine Dakhama, Bodduluri Haribabu, Erwin W. Gelfand

JOURNAL OF IMMUNOLOGY 181 ( 2 ) 1170 - 1178 2008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 ASSOC IMMUNOLOGISTS

Dendritic cells (DC) are important APCs that control allergen-induced airway responses by interacting directly with T cells. Leukotriene B(4) (LTB(4)), interacting with its high-affinity receptor, LTB4 receptor 1 (BLT1), is known to attract and activate leukocytes during inflammation. We have previously shown that BLT1 expression on Ag-primed T cells is required for the development of airway hyperresponsiveness (AHR; Miyahara et al. 2005. Am. J. Respir. Crit. Care Med. 172: 161-167). However, the role for the LTB(4)-BLT1 pathway in DC function in allergen-induced airway responses has not been defined. Bone marrow-derived DCs (BMDC) were generated. Naive BALB/c mice received OVA-pulsed BLT1-deficient (BLTI(-/-)) BMDCs or wild-type BMDCs intratracheally and were then challenged with OVA for 3 days. Airway responses were monitored 48 h after the last allergen challenge. BLTI(-/-) BMDCs showed normal maturation judged from surface expression of CD markers. Compared with recipients of wild-type BMDCs, mice that received BLT1(-/-) BMDCs developed significantly lower AHR to inhaled methacholine, lower goblet cell metaplasia, and eosinophilic infiltration in the airways and decreased levels of Th2 type cytokines in the bronchoalveolar lavage fluid. Migration of BLTI(-/-) BMDCs into peribronchial lymph nodes was significantly impaired compared with BLTI(+/+) BMDCs after intratracheal instillation. These data suggest that BLTI expression on DCs is required for migration of DCs to regional lymph nodes as well as in the development of AHR and airway inflammation.

DOI： 10.4049/jimmunol.181.2.1170

Evidence that CD8(+) dendritic cells enable the development of gamma delta T cells that modulate airway hyperresponsiveness 査読

Laura Cook, Nobuaki Miyahara, Niyun Jin, J. M. Wands, Christian Taube, Christina L. Roark, Terry A. Potter, Erwin W. Gelfand, Rebecca L. O'Brien, Willi K. Born

JOURNAL OF IMMUNOLOGY 181 ( 1 ) 309 - 319 2008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 ASSOC IMMUNOLOGISTS

Airway hyperresponsiveness (AHR), a hallmark of asthma and several other diseases, can be modulated by gamma delta T cells. In mice sensitized and challenged with OVA, AHR depends on allergen-specific alpha beta T cells; but V gamma 1(+) gamma delta T cells spontaneously enhance AHR, whereas V gamma 4(+) gamma delta T cells, after being induced by airway challenge, suppress AHR. The activity of these gamma delta T cell modulators is allergen nonspecific, and how they develop is unclear. We now show that CD8 is essential for the development of both the AHR suppressor and enhancer gamma delta T cells, although neither type needs to express CD8 itself. Both cell types encounter CD8-expressing non-T cells in the spleen, and their functional development in an otherwise CD8-negative environment can be restored with transferred spleen cell preparations containing CD8(+) dendritic cells (DCs), but not CD8(+) T cells or CD8-DCs. Our findings suggest that CD8(+) DCs in the lymphoid tissues enable an early step in the development of gamma delta T cells through direct cell contact. DC-expressed CD8 might take part in this interaction.

DOI： 10.4049/jimmunol.181.1.309

Plasticity of regulatory T cells: Subversion of suppressive function and conversion to enhancement of lung allergic responses 査読

Anthony Joetham, Shigeki Matsubara, Masakazu Okamoto, Katsuyuki Takeda, Nobuaki Miyahara, Azzeddine Dakhama, Erwin W. Gelfand

JOURNAL OF IMMUNOLOGY 180 ( 11 ) 7117 - 7124 2008年6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

Activation of CD4(+)CD25(+)Foxp3(+) naturally occurring regulatory T cells (nTregs) resulting in suppression of lung allergic responses requires interaction of MHC class I on nTregs and CD8. In the absence of CD8 (CD8(-/-) recipients), transferred nTregs restored airway hyperresponsiveness, eosinophilic inflammation, and IL-13 levels following allergen exposure. Enhancement of lung allergic responses was accompanied by reduced expression of Foxp3 and increased expression of IL-13 in the transferred nTregs. In CD8(-/-) recipients pretreated with glucocorticoid-induced TNFR-related protein-ligand Ab, the transferred nTregs maintained high levels of Foxp3 and did not result in altered lung responses. Thus, the regulatory function of nTregs can be subverted by reducing the expression of Foxp3 and following signaling through glucocorticoid-induced TNFR-related protein are converted nTregs into IL-13-producing CD4(+) T cells mediating lung allergic responses.

DOI： 10.4049/jimmunol.180.11.7117

Estrogen determines sex differences in airway responsiveness after allergen exposure 査読

Shigeki Matsubara, Christina H. Swasey, Loan E. Loader, Azzeddine Dakhama, Anthony Joetham, Hiroshi Ohnishi, Annette Balhorn, Nobuaki Miyahara, Katsuyuki Takeda, Erwin W. Gelfand

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY 38 ( 5 ) 501 - 508 2008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：AMER THORACIC SOC

The female hormone estrogen is an important factor in the regulation of airway function and inflammation, and sex differences in the prevalence of asthma are well described. Using an animal model, we determined how sex differences may underlie the development of altered airway function in response to allergen exposure. We compared sex differences in the development of airway hyperresponsiveness (AHR) after allergen exposure exclusively via the airways. Ovalbumin (OVA) was administered by nebulization on 10 consecutive days in BALB/c mice. After methacholine challenge, significant AHR developed in male mice but not in female mice. Ovariectomized female mice showed significant AHR after 10-day OVA inhalation. IC11182,780, an estrogen antagonist, similarly enhanced airway responsiveness even when administered 1 hour before assay. In contrast, 17 beta-estradiol dose-dependently suppressed AHR in male mice. In all cases, airway responsiveness was inhibited by the administration of a neurokinin I receptor antagonist. These results demonstrate that sex differences in 10-day OVA-induced AHR are due to endogenous estrogen, which negatively regulates airway responsiveness in female mice. Cumulatively, the results suggest that endogenous estrogen may regulate the neurokinin 1-dependent prejunctional activation of airway smooth muscle in allergen-exposed mice.

DOI： 10.1165/rcmb.2007-0298OC

ゲフィチニブ単剤療法が施行された肺非小細胞癌における予後因子としての血清KL-6

藤原義朗, 木浦勝行, 瀧川奈義夫, 豊岡伸一, 堀田勝幸, 宗淳一, 宮原信明, 谷本安, 金廣有彦, 田端雅弘, 加藤勝也, 伊達洋至, 谷本光音

日本呼吸器学会雑誌 46 ( 増刊 ) 131 - 131 2008年5月

Corticosteroids enhance CD8(+) T cell-mediated airway hyperresponsiveness and allergic inflammation by upregulating leukotriene B-4 receptor 1 査読

Hiroshi Ohnishi, Nobuaki Miyahara, Azzeddine Dakhama, Katsuyuki Takeda, Steven Mathis, Bodduluri Haribabu, Erwin W. Gelfand

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 121 ( 4 ) 864 - 871 2008年4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: Leukotriene B-4 (LTB4) is a potent inflammatory lipid mediator that binds to LTB4 receptor 1 (BLT1). Ligation of BLT1 by LTB4 plays an important role in the recruitment of effector memory CD8(+) T cells into the airways of sensitized and challenged mice.
Objectives: The effects of the corticosteroid dexamethasone (DEX) on BLT1-expressing effector memory CD8(+) T cells and effector memory CD8(+) T cell-mediated airway hyperresponsiveness (AHR) and allergic inflammation were determined.
Methods: Effector memory CD8(+) T cells were generated from ovalbumin(257-264)-primed mononuclear cells from OT-1 mice in the presence of IL-2. In some cultures DEX was added. The effects of DEX on BLT1 expression, LTB4-induced Ca2+ influx, phosphorylation of extracellular signal-regulated kinase 1/2, chemotaxis, and effector memory CD8(+) T cell-mediated AHR were examined.
Results: DEX-treated effector memory CD8(+) T cells showed significant increases in surface expression of BLT1, LTB4-induced intracellular Ca2+ influx, phosphorylation of extracellular signal-regulated kinase 1/2, and chemotaxis. Upregulation of BLT1 by DEX was accompanied by increased IL-2 receptor expression. Adoptive transfer of DEX-treated effector memory CD8(+) T cells into ovalbumin-sensitized and ovalbumin-challenged CD8(-/-) mice resulted in significant increases in AHR, allergic inflammation, goblet cell metaplasia, and numbers of both CD8(+) and CD4(+) T cells in the bronchoalveolar lavage fluid and lungs.
Conclusions: Corticosteroids upregulate BLT1 on effector memory CD8(+) T cells and related signaling pathways and potentiate allergic airway inflammation and AHR induced by these cells.

DOI： 10.1016/j.jaci.2008.01.035

Contribution of allergen-specific and nonspecific nasal responses to early-phase and late-phase nasal responses 査読

Satoko Miyahara, Nobuaki Miyahara, Joseph J. Lucas, Anthony Joetham, Shikegi Matsubara, Hiroshi Ohnishi, Azzeddine Dakhama, Erwin W. Gelfand

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 121 ( 3 ) 718 - 724 2008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：MOSBY-ELSEVIER

Background: The relative contributions of the allergen-specific early-phase nasal response and nonspecific nasal response and mast cells to the pathophysiology of allergic rhinitis are not well defined.
Objectives: To determine the contributions of specific reactivity, nonspecific reactivity, and mast cells to the development of early-phase and late-phase responses using a mouse model of allergic rhinitis.
Methods: Sensitized wild-type and Fc epsilon RI-deficient (FC epsilon RI(-/-)) mice were exposed to allergen for 3, 5, or 12 days. As indicators of nasal reactivity, respiratory frequency and nasal resistance were monitored.
Results: Sensitized mice exposed to 3 days of nasal allergen challenge showed a nonspecific early-phase response. As the number of allergen exposures increased, there was progressive diminution in nonspecific responses with increased allergen-specific early-phase responses and a late-phase response. Sensitized Fc epsilon RI(-/-) mice did not develop nonspecific nasal responses or late-phase responses, but transfer of in vitro-differentiated wild-type mast cells into Fc epsilon RI(-/-) mice restored nonspecific early-phase nasal responses but not the late-phase response.
Conclusion: These data identify the nonspecific nasal response as a major contributor to the early-phase response, especially during initial allergen exposure, and is dependent on mast cells. Increasing allergen exposure results in increasing allergen-specific responses, converting the nonspecific early-phase response to a late-phase response that is allergen-specific and mast cell-independent.

DOI： 10.1016/j.jaci.2007.11.002