免疫系ホメオスターシスを制御するシグナルの解析

• Project/Area Number: 13140204
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Osaka University
• Principal Investigator: 菊谷 仁 大阪大学, 微生物病研究所, 教授 (80161412)
• Co-Investigator(Kenkyū-buntansha): 安居 輝人 大阪大学, 微生物病研究所, 助手 (60283074)
• Project Period (FY): 2001 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥142,500,000 (Direct Cost: ¥142,500,000); Fiscal Year 2005: ¥30,000,000 (Direct Cost: ¥30,000,000); Fiscal Year 2004: ¥30,000,000 (Direct Cost: ¥30,000,000); Fiscal Year 2003: ¥27,000,000 (Direct Cost: ¥27,000,000); Fiscal Year 2002: ¥27,000,000 (Direct Cost: ¥27,000,000); Fiscal Year 2001: ¥28,500,000 (Direct Cost: ¥28,500,000)
• Keywords: Th1反応 / Th2反応 / Sema4A / Sema6D / Plexin-A1 / T細胞 / 樹状細胞 / Th1細胞 / CD100 / セマフォリン / plexin / Th1 / 心臓形態形成 / 副刺激分子 / 抗原提示細胞 / NODマウス / 自己免疫 / 自己抗原 / 免疫 / B細胞 / CD72

Research Abstract

セマフォリンファミリーは、神経回路形成過程において機能するガイダンス因子として同定された分子群であるが、申請者らの研究から、種々のセマフォリン分子が免疫反応の成立や調節において重要な役割を果たしていることが明らかになってきた。本研究は、これら分子のin vitro、in vivoにおける免疫学的活性、それらの受容体の同定やシグナル伝達経路の解析を行い、本年度は以下の研究成果を得た。
(1)昨年度までに、Sema4A欠損マウスを作成とその解析から、樹状細胞上のSema4AがT細胞のプライミングにおいてT細胞上のSema4AがTh1分化において必要であることを示した。本年度は、遺伝的背景がBALB/cのSema4A欠損マウスを解析し、Sema4A非存在下ではTh2反応が亢進し、アレルギー様の皮膚炎が自然発症することが明らかになった。また、ヒトの多発性硬化症により近い自己免疫性脳脊髄炎(EAE)を発症するSJLマウスを用いて、抗Sema4A抗体による発症阻止実験を行った。その結果、抗Sema4A抗体がSJLマウスにおける再発性の脳脊髄炎の発症を阻止できることを示した。
(2)昨年度作成したPlexin-A1欠損マウスを更に詳細に解析した。その結果、Plexin-A1欠損マウスにおいては樹状細胞の機能や抗原特異的なT細胞分化が著しく低下しているのに加え、破骨細胞の分化不全から大理石病を発症することが明らかになった。また、Plexin-A1欠損樹状細胞はSema6Dに対する結合性や、Sema6Dによるサイトカイン産生が著明に減弱しており、樹状細胞の活性化においてSema6D-Plexin-A1相互作用が重要な働きを果たしていると考えられる。

Research Products

• [Journal Article] The FERM domain containing GEF protein FARP2 triggers signals for Sema3A-mediated axonal repulsion. (2005)
  • Author(s): Toyofuku, T., Kikutani, H., et al.
  • Journal Title: Nature Neurosci 8 Pages: 1712-1719
• [Journal Article] Loss of Dopaminerigc Neurons by the induction of inducible nitric oxide synthase and cyclooxygenase-2 via CD40: Relevance to Parkinson's disease. (2005)
  • Author(s): Okuno, T., Kikutani, H., et al.
  • Journal Title: J.Neurosci.Res 81 Pages: 874-882
• [Journal Article] Semaphoris: a new class of immunoregulatory molecules. (2005)
  • Author(s): Takegahara, N., Kumanogoh, A., Kikutani, H.
  • Journal Title: Philos.Trans.R.Soc.Lond B.Biol.Sci 360 Pages: 1673-168
• [Journal Article] Requirement for CD100-CD72 interactions in fine-tuning of B-cell antigen receptor signaling and homeostatic maintenance of the B-cell compartment. (2005)
  • Author(s): Kumanogoh, A., Kikutani, H., et al.
  • Journal Title: Int.Immunol. 17 Pages: 1277-1282
  • NAID: 10016810755
• [Journal Article] Semaphorin 4A induces growth cone collapse of hippocampal neurons in a Rho/Rho-kinase-dependent manner. (2005)
  • Author(s): Yukawa, K., Kikutani, H., et al.
  • Journal Title: Int.J.Mol.Med. 16 Pages: 115-118
• [Journal Article] Non-redundant roles of Sema4A in the immune system : Defective T-cell priming and Th1/Th2 regulation in sema4A-deficient mice. (2005)
  • Author(s): Kumanogoh, A., H.Kikutani, et al.
  • Journal Title: Immunity 22 Pages: 1-12
• [Journal Article] Guidance of myocardial patterning in cardiac development by Sema6D reverse signaling. (2004)
  • Author(s): T Toyofuku, T., A.Kumanogoh, H.Kikutani, et al.
  • Journal Title: Nature Cell Biol. 6 Pages: 1204-1211
• [Journal Article] Dual roles of Sema6D in cardiac morphogenesis through region-specific association of its receptor, Plexin-Al, with off-track and vascular endothelial growth factor receptor type 2. (2004)
  • Author(s): T Toyofuku, T., A.Kumanogoh, H.Kikutani, et al.
  • Journal Title: Genes & Dev. 18 Pages: 435-447
• [Journal Article] Biological functions and signaling of a transmembrane semaphorine, CD 100/Sema4A. (2004)
  • Author(s): Kumanogoh, A., H.Kikutani.
  • Journal Title: Cell Mol.Life Sci. 61 Pages: 292-300
• [Publications] Toyofuku T, Zhang H, Kumanogoh A, H.Kikutani, et al.: "Dual roles of Sema6D in cardiac morphogenesis through region-specific association of its receptor, Plexin-A1, with off-tack and vascular endothelial growth factor receptor type 2."Genes Dev.. 18. 435-447 (2004)
• [Publications] Kumanogoh A, Kikutani H.: "Biological functions and signals of CD100/Sema4D."Cell Mol life Sci.. 61. 292-300 (2004)
• [Publications] Kumanogoh A, Kikutani H.: "Roles of the semaphorin family in immune regulation."Adv.Immunol.. 81. 173-198 (2003)
• [Publications] Kumanogoh A, Kikutani H.: "Immune semaphorins : a new area of semaphorin research."J.Cell Sci. 116. 3463-3470 (2003)
• [Publications] Ishida I, Kumanogoh, A., Suzuki K, Akahani S, Noda K, Kikutani H.: "Involvement of CD100, a lymphocyte semaphorin, in the activation of the human immune system via CD72 : implications for the regulation of immune and inflammatory responses."Int.Immunol.. 15. 1027-1034 (2003)
• [Publications] Kikutani H, Kumanogoh A.: "Semaphorins in T cell-antigen presenting cell interactions."Nat.Rev.Immunol.. 3. 159-167 (2003)
• [Publications] Kikutani, H., A.Kumanogoh: "Semaphorins in interactions between T cells and antigen-presenting cells"Nature Rev. Immunol.. 3. 159-167 (2003)
• [Publications] Suzuki, K., A.Kumanogoh, H.Kikutani: "CD100/Sema4D, a lymphocyte semaphoring involved in the regulation of humoral and cellular immune responses"Cytokine Growth Factor Rev.. 14. 17-24 (2003)
• [Publications] Kumanogoh., A., H.Kikutani, et al.: "Sema4A, a class IV semaphoring that enhacens T cell activation, interacts with Tim-2"Nature. 419. 629-633 (2002)
• [Publications] Kumanogoh, A., H.Kikutani, et al.: "Requirement for the lymphocyte semaphoring, CD100, in the induction of antigen-specific T cells and the maturation of dendritic cells"J. Immunol.. 169. 1175-1181 (2002)
• [Publications] Yasui, T., A.Kumanogoh, H.Kikutani, et al.: "Dissection of B cell differentiation during primary immune responses in mice with altered CD4O signals"Int. Immunol.. 14. 319-329 (2002)
• [Publications] Yoshida, K., H.Kikutani, et al.: "Evidence for shared recognition of peptide ligand by a diverse panel of nonobese diabeteic (NOD) mice-derived, islet-specific, diabetogenic T cell clones"Int. Immunol.. 14. 1439-1447 (2002)
• [Publications] Yasui, T., Kikutani, H., et al.: "Dissection of B cell differentiation during primary immune responses in mice with altered CD40 signals"Int.Immunol.. 14. 319-329 (2002)
• [Publications] Kumanogoh, A., Kikutani, H., et al.: "The CD100/Sema4D-CD72 interactions : a novel mechanism of immune regulation"Trends in Immunology (formerly known as "Immunology Today"). 22. 670-676 (2001)
• [Publications] Watanabe, C., Kikutani, H., et al.: "Enhanced immune responses in transgenic mice expressing a truncated form of the lymphocyte semaphorin CD100"J.Immunol.. 167. 4321-4328 (2001)
• [Publications] Kumanogoh, A., Kikutani, H.et al.: "Increased T-cell autoreactivity in the absence of CD40-CD40 ligand interactions : A role of CD40 in regulatory T cell development"J.Immunol.. 166. 353-360 (2001)
• [Publications] Wang, X.-S., Kikutani, H., et al.: "Functional soluble CD100/Sema4D released from activated lymphocytes : Possible role in normal and pathological immune responses"Blood. 97. 3498-3504 (2001)
• [Publications] Kishimoto, T., Kikutani, H.: "Knocking the SOCS off a tumor suppressor"Nature Genetics. 28. 4-5 (2001)