ホメオスターシスと自己寛容に関わるT細胞補助刺激分子の機能解析とその人為的制御

• Project/Area Number: 13140201
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: 東 みゆき 東京医科歯科大学, 大学院・医歯学総合研究科, 教授 (90255654)
• Co-Investigator(Kenkyū-buntansha): 橋口 昌章 東京医科歯科大学, 大学院・医歯学総合研究科, 助手 (20372443) ; 小園 裕子 東京医科歯科大学, 歯学部付属病院, 助手 (30197107)
• Project Period (FY): 2001 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥135,100,000 (Direct Cost: ¥135,100,000); Fiscal Year 2005: ¥26,300,000 (Direct Cost: ¥26,300,000); Fiscal Year 2004: ¥26,300,000 (Direct Cost: ¥26,300,000); 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: 補助シグナル分子 / 免疫制御 / B7ファミリー / 制御性T細胞 / 樹状細胞 / 免疫学 / ホメオスターシス / 免疫寛容 / T細胞 / 免疫応答 / 抑制分子 / 免疫細胞 / 自己免疫 / B7 / 抑制シグナル分子

Research Abstract

エフェクターT細胞による臓器特異的な局所免疫応答においては、B7補助シグナル経路が正および負に免疫応答を調節していることを多くのマウス疾患モデルを用いた検討から明らかにしてきた.本年は、PD-1:B7-H1抑制経路に加え、BTLA,B7-H3,B7-H4経路の機能について検討を行なった.また、エフェクターT細胞と制御性T細胞のそれぞれに対する補助刺激分子の関わりという視点からも解析を進めた.炎症時に局所組織細胞に誘導されるB7-H1の機能を明らかにするために、角化細胞特異的にB7-H1を発現させたトランスジェニックマウスを作成した.ハプテン抗原を用いた接触性過敏反応において、早期応答と遅延型応答にB7-H1が異なって関与していることを示す結果を得た.また、B7-H3およびB7-H4の機能解析において、in vivoおよびin vitroにおける抗体を用いた分子機能解析結果は、これらのシグナル経路がB7-H1/B7-DCと同様に免疫応答を正または負に複雑に制御する可能性を示した.この複雑な機構の理由のひとつとして、制御性T細胞の関与が示唆された.Co-stimulatorであるCD28とGITR、Co-inhibitorであるPD-1とBTLAは、conventionalなCD25^-CD4^+エフェクターT細胞に対してのみならず、CD25^-CD4^+制御性T細胞に対しても増殖および機能調節Co-signal分子として働くこと、in vivoにおいては組織樹状細胞あるいは組織細胞と制御性T細胞間相互作用において調節されていることが示唆された.

Research Products

• [Journal Article] Predominant expression of B7-H1 and its immunoregulatory roles in oral squamous cell carcinoma. (2006)
  • Author(s): Tsushima F, Tanaka K, et al.
  • Journal Title: Oral Oncol 42(3) Pages: 268-274
• [Journal Article] Expression and regulation of human CD275 on endothelial cells in healthy and inflamed mucosal tissues. (2006)
  • Author(s): Youngnak-Piboonratanakit p, Tsushiina F, et al.
  • Journal Title: J.Immunol 63 Pages: 191-198
• [Journal Article] Role of the programmed death-1 (PD-1) pathway in regulation of alloimmune responses in vivo. (2005)
  • Author(s): Sandner SE, Clarkson MR, et al.
  • Journal Title: J.Immnuol 174 Pages: 3408-3415
• [Journal Article] Clinical significance of PD-L1 and PD-L2 expression in human esophageal cancer. (2005)
  • Author(s): Ohigashi Y, Sho M, et al.
  • Journal Title: Cancer Res 11(8) Pages: 2947-2953
• [Journal Article] A-critical role for the programmed death ligand 1 in fetomaternal tolerance. (2005)
  • Author(s): Guleria I, Khousroshahi A, et al.
  • Journal Title: J.Exp.Med 202 Pages: 231-237
• [Journal Article] Blockade of B7-H1 on macrophages suppresses CD4^+ T cell proliferation by augmenting IFN-γ-induced nitric oxide production. (2005)
  • Author(s): Yamazaki T, Akiba H, et al.
  • Journal Title: J.Immunol 175 Pages: 1586-1592
• [Journal Article] Role of the programmed death-1 (PD-1) pathway in regulation of alloimmune responses in vivo. (2005)
  • Author(s): Sandner SE et al.
  • Journal Title: J.Immunol. (in press)
• [Journal Article] B7-DC regulates asthmatic responses by interferon-g-dependent mechanism. (2004)
  • Author(s): Matsumoto K et al.
  • Journal Title: J.Immunol. 172 Pages: 2530-2541
• [Journal Article] Costimulation via glucocorticoid-induced tumor necrosis factor receptor (GITR) in both conventional and CD25^+ regulatory CD4^+ T cells. (2004)
  • Author(s): Kanamaru F et al.
  • Journal Title: J.Immunol. 172 Pages: 7306-7314
• [Journal Article] B7-H1 expression in non-small cell lung cancer and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. (2004)
  • Author(s): Konishi J et al.
  • Journal Title: Clin.Cancer Res. 10 Pages: 5094-5100
• [Journal Article] Expression of membrane-bound and soluble receptor activator of NF-κB ligand (RANKL) in human T cells. (2004)
  • Author(s): Kanamaru F et al.
  • Journal Title: Immunol.Let. 94(3) Pages: 239-246
• [Journal Article] The expression of B7-H1 on keratinocytes in chronic inflammatory mucocutaneous disease and its regulatory role. (2004)
  • Author(s): Youngnak-Piboonratanakit P et al.
  • Journal Title: Immunol.Let. 94(3) Pages: 215-222
• [Publications] Ansari M J: "The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in Nonobese Diabetic (NOD) mice."J.Exp.Med.. 198. 63-69 (2003)
• [Publications] Shin T: "Cooperative B7-1/2 (CD80/CD86) and B7-DC (PD-L2) costimulation of CD4 T cells independent of the PD-1 receptor."J.Exp.Med.. 198. 31-38 (2003)
• [Publications] Pornpan Y: "Differential binding properties of B7-H1 and B7-DC to programmed death-1 (PD-1)."BBRC. 307. 672-677 (2003)
• [Publications] Tsushima F: "Involvement of Programmed Death-1-mediated Regulation in Murine Contact Hypersensitivity."Eur.J.Immunol. 33. 2773-2783 (2003)
• [Publications] Iwai H: "Involvement of inducible costimulator-B7 homologous protein costimulatory pathway in murine lupus nephritis."J.Immunol. 171. 2848-2854 (2003)
• [Publications] Kanai T: "Blockade of B7-H1 suppresses the development of chronic intestinal inflammation."J.Immunol. 171. 4156-4163 (2003)
• [Publications] Seko Y, Azuma M et al.: "Expression of tumor necrosis factor ligand superfamily costimulatory molecules CD27L, CD30L, OX40L and 4-1BBL in the heart of patients with acute myocarditis and dilated cardiomyopathy"Cardiovasc Pathol. 11. 166-170 (2002)
• [Publications] Mogi S, Azuma M et al.: "The effect of recombinant CD80-Adenovirus and interleukin-12 on generation of cytotoxic T lymphocytes against autologous tumour in patients with oral squamous cell carcinoma"Asian J Oral Maxillofac Surg. 14. 87-94 (2002)
• [Publications] Ohata J, Azuma M et al.: "Differential graft-versus-leukemia effect by CD28 and CD40 co-stimulatory blockade after graft-versus-host disease prophylaxis"Clin Exp Immunol. 129. 61-68 (2002)
• [Publications] Iwai H, Azuma M et al.: "Amelioration of collagen-induced arthritis by blockade of ICOS-B7h costimulation"J Immunol.. 169. 4332-4339 (2002)
• [Publications] Yamazaki T, Azuma M et al.: "Expression of PD-1 ligands by murine T cells and antigen-presenting cells"J Immunol.. 169. 5538-5545 (2002)
• [Publications] Totsuka T, Azuama M et al.: "Ameliorating effect of anti-Inducible Co-stimulator monoclonal antibody in a murine model of chronic colitis"Gastroenterology. 124. 410-421 (2003)
• [Publications] Hattori, H.: "Expression of costimulatory CD80/CD86-CD28/CD152 molecules in nasal mucosa of patients with perennial allergic rhinitis"Clin.Exp.Allergy. 31. 1242-1249 (2001)
• [Publications] Nuriya, S.: "The role of CTLA-4 in murine contact hypersensivity"J.Invest.Dermatol.. 116. 764-768 (2001)
• [Publications] Ebata, T.: "Rapid induction of CD95 ligand and CD4^+ T cell-mediated apoptosis by CD137 (4-1BB) costimulation"Eur.J.Immunol.. 31. 1410-1416 (2001)
• [Publications] Nozawa, K.: "Preferential blockade of CD8^+ T Cell responses by administration of anti-CD137 ligand monoclonal antibody results in differential effect on development of murineacute and chronic graft-vs-host diseases"J.Immunol.. 167. 4981-4986 (2001)
• [Publications] Guo, Z.: "Immunotherapy with nondepleting anti-CD4 monoclonal antibodies but not CD28 antagonists protects islet graft in spontaneously diabetic NOD mice from autoimmune destruction and allogeneic an zenogeneic graft rejection"Transplantation. 71. 1656-1665 (2001)
• [Publications] Okano, M.: "Differential role of CD8O and CD86 molecules in the induction and the effector phases of allergic rhinitis in mice"Am.J.Respir.Crit.Care.Med.. 164. 1501-1507 (2001)