1996 Fiscal Year Annual Research Report

免疫識別と応答の多様性の分子機構

Research Project

Project/Area Number	08282104
Research Category	Grant-in-Aid for Scientific Research on Priority Areas
Research Institution	Kyushu University
Principal Investigator	笹月健彦九州大学, 生体防御医学研究所, 教授 (50014121)
Co-Investigator(Kenkyū-buntansha)	笠原正典北海道大学, 医学部, 助教授 (30241318) 稲葉カヨ京都大学, 理学部, 助教授 (00115792) 吉開泰信名古屋大学, 医学部, 教授 (90158402) 西村泰治熊本大学, 大学院・医学研究科, 教授 (10156119) 菊谷仁大阪大学, 微生物病研究所, 教授 (80161412)
Keywords	HLA / CD40 / 自己免疫疾患 / 樹状細胞 / γδT細胞 / NK1.1 / プロテアソーム
Research Abstract	MHCとペプチドの特異的結合、MHC/ペプチド複合体のTCRによる認識およびそれに引き続く免疫応答とその制御機構を明らかにし、それに基づき免疫異常発症機能の解明への道を拓くことを目的として以下の知見を得た。 1)HBs抗原に対する抗体価とHLAクラスI、クラスII対立遺伝子頻度との相関を解析することで、特定のHLAクラスI分子(HLA-A2602)が抗体産生を負に制御する可能性を示した。また新しいT細胞エピトープの同定に関する方法論を樹立した。 2)CD40欠損NODマウスを作製し、自己反応性T細胞の分化・活性化にCD40-CD40L相互作用が必項であることを明らかにした。またTCRトランスジェニックマウスを用いてTh1細胞の出現にCD40が必要であることを示した。 3)多発性硬化症(MS)を脊髄・視神経の病巣を特徴とするアジア型と大脳に病巣を多発する西洋型とに分類し、HLAクラスII対立遺伝子頻度との相関を検討することで両型の免疫遺伝学的要因が異なることを明らかにした。また東洋人に特有のHLA-DR9-DQ9およびDR13-DQ6と強い相関を示す乳幼児発症重症筋無力症の患者より、HLA-DQ6分子により提示されるアセチルコリンレセプターα鎖由来のペプチドに反応性を示すTh1様細胞クローンを樹立した。 4)マウスサルモネラ感染症におけるγδ型T細胞サブセットの特異性と機能について検討した。感染後、腹腔内に増加するNK1.1^+γδ型T細胞はVγ4/Vδ4を発現しており、MHCクラスII分子を認識して、IL-4を産生するが、NK1.1^-γδ型T細胞は、サルモネラ抗原を認識して、γIFNを産生することを明らかにした。 5)内因性のタンパク抗原であるEαペプチドは胸腺樹状細胞だけでなく、未梢リンパ組織のT細胞領域の相互嵌入樹状細胞(IDC)にも多量に発現されており、特異的T細胞株の活性化と同時にactivation-induced cell deathを誘導することを明らかにした。 6)MHCクラスI分子によって提示されるペプチドの産生に与るプロテアーゼであるプロテアソームのサブユニット遺伝子を解析することにより、ヒトやマウスを初めとする脊椎動物のゲノムにはMHCのコピーともいえる遺伝領域が存在することを示した。

Research Products
(17 results)

All Other

All Publications (17 results)

[Publications] Fukui Y.: "Positive and negative CD4+ thymocyte selection by a single MHC class II/peptide ligand in vivo affected by its expression level in the thymus." Immunity. (in press).
[Publications] Yamaguchi Y.: "Contrasting effect of TGFβ1 and TNFα on the development of dendritic cells from progenitors in mouse bone marrow." Stem Cells. (in press).
[Publications] Enomoto A.: "Predominant appearance of NK1.1+ T cells producing IL-4 in the peritoneal cavity of mice with beige mutation curing Salmonella infection." J.Immunol.158. 2268-2277 (1997)
[Publications] Mineta M.: "Contribution of HLA class I and class II alleles to the regulation of antibody Productionto hepatitis B surface antigen in humans." Int.Immunol.8. 525-531 (1996)
[Publications] Hori T.: "Japanese cedar pollinosis and HLA-DP5." Tissue Antigens. 47. 485-491 (1996)
[Publications] Kamanaka M.: "Protective role of CD40 in Leishmania major infection at two distinc phases of cell-mediated immunity." Immunity. 4. 275-281 (1996)
[Publications] Moritani M.: "Prevention of adoptively transferred diabetes in non-obese diabetic mice with IL-10-transduced islet-specific Th1 lymphocytes:Gene therapy model for autoimmune Labetes." J.Clinc.Invest.98. 1851-1859 (1996)
[Publications] Nagasawa T.: "Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1." Nature. 382. 635-638 (1996)
[Publications] Kira J-I.: "Western vs. Asian types of multiple sclerosis: immunogenetically and clinically distinct disorders." Ann. Neurol.40. 569-574 (1996)
[Publications] Chen Y-Z.: "Response of a human T cell clone to a large panel of altered peptide ligands carrying single residue substitutions in an antigenic peptide;characterization and frequencles of TCR agonism and TCR antagonism with or without partial activation." J.Immunol.157. 3783-3790 (1996)
[Publications] Matsuoka T.: "Altered TCR ligands affect antigen-presenting cell responses:Uprerulation of IL-12 by an analogue peptide." J.Immunol.157. 4837-4843 (1996)
[Publications] Nishimura H.: "IL-5 is novel growth factor for murineγδ T cells induced by Salmonella infection." J.Immunol.156. 663-669 (1996)
[Publications] Ortner U.: "An improved method to obtain murine migratory cutaneous dendritic cells." J.Immunol.Methods. 193. 71-79 (1996)
[Publications] Fazle Akbar S.M.: "Upregulation of MHC class II antigen on dendritic cells from hepatitis B virus transgenic mice by γ-interferon:abrogation of immune response defect to a T cell-dependent antigens." Immunology. 87. 519-527 (1996)
[Publications] Kasahara M.: "Chromosomal localization of the mouse proteasome Z subunit gene reveals an ancient chromosomal duplication involving the major histocompatibility complex." Proc.Natl.Acad.Sci.U.S.A.93. 9096-9101 (1996)
[Publications] Kandil E.: "Isolation of low molecular mass polypeptide complementary DNA clones from primitive vertebrates:Implications for the origin of MHC class I-restricted antigen presentation." J.Immunol.156. 4245-4253 (1996)
[Publications] Kasahara M.: "Origine and evolution of the class I gene family:Why are some of the mammalian class I genes encoded outside the major histocompatibility complex?" Res.Immunol.147. 278-284 (1996)

1996 Fiscal Year Annual Research Report

免疫識別と応答の多様性の分子機構

Principal Investigator

笹月 健彦 九州大学, 生体防御医学研究所, 教授 (50014121)

Research Products

[Publications] Fukui Y.: "Positive and negative CD4+ thymocyte selection by a single MHC class II/peptide ligand in vivo affected by its expression level in the thymus." Immunity. (in press).

[Publications] Yamaguchi Y.: "Contrasting effect of TGFβ1 and TNFα on the development of dendritic cells from progenitors in mouse bone marrow." Stem Cells. (in press).

[Publications] Enomoto A.: "Predominant appearance of NK1.1+ T cells producing IL-4 in the peritoneal cavity of mice with beige mutation curing Salmonella infection." J.Immunol.158. 2268-2277 (1997)

[Publications] Mineta M.: "Contribution of HLA class I and class II alleles to the regulation of antibody Productionto hepatitis B surface antigen in humans." Int.Immunol.8. 525-531 (1996)

[Publications] Hori T.: "Japanese cedar pollinosis and HLA-DP5." Tissue Antigens. 47. 485-491 (1996)

[Publications] Kamanaka M.: "Protective role of CD40 in Leishmania major infection at two distinc phases of cell-mediated immunity." Immunity. 4. 275-281 (1996)

[Publications] Moritani M.: "Prevention of adoptively transferred diabetes in non-obese diabetic mice with IL-10-transduced islet-specific Th1 lymphocytes:Gene therapy model for autoimmune Labetes." J.Clinc.Invest.98. 1851-1859 (1996)

[Publications] Nagasawa T.: "Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1." Nature. 382. 635-638 (1996)

[Publications] Kira J-I.: "Western vs. Asian types of multiple sclerosis: immunogenetically and clinically distinct disorders." Ann. Neurol.40. 569-574 (1996)

[Publications] Matsuoka T.: "Altered TCR ligands affect antigen-presenting cell responses:Uprerulation of IL-12 by an analogue peptide." J.Immunol.157. 4837-4843 (1996)

[Publications] Nishimura H.: "IL-5 is novel growth factor for murineγδ T cells induced by Salmonella infection." J.Immunol.156. 663-669 (1996)

[Publications] Ortner U.: "An improved method to obtain murine migratory cutaneous dendritic cells." J.Immunol.Methods. 193. 71-79 (1996)

[Publications] Fazle Akbar S.M.: "Upregulation of MHC class II antigen on dendritic cells from hepatitis B virus transgenic mice by γ-interferon:abrogation of immune response defect to a T cell-dependent antigens." Immunology. 87. 519-527 (1996)

[Publications] Kasahara M.: "Chromosomal localization of the mouse proteasome Z subunit gene reveals an ancient chromosomal duplication involving the major histocompatibility complex." Proc.Natl.Acad.Sci.U.S.A.93. 9096-9101 (1996)

[Publications] Kandil E.: "Isolation of low molecular mass polypeptide complementary DNA clones from primitive vertebrates:Implications for the origin of MHC class I-restricted antigen presentation." J.Immunol.156. 4245-4253 (1996)

[Publications] Kasahara M.: "Origine and evolution of the class I gene family:Why are some of the mammalian class I genes encoded outside the major histocompatibility complex?" Res.Immunol.147. 278-284 (1996)

笹月健彦九州大学, 生体防御医学研究所, 教授 (50014121)