Analyzes on artifical induction of antigen-specific immunological tolerance

人工诱导抗原特异性免疫耐受的分析

• 批准号: 05454211
• 负责人: YAGITA Hideo
• 金额: $ 4.16万
• 依托单位: Juntendo University, School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05454211/
• 关键词: tolerance; transplantation; autoimmune disease; LFA-1; ICAM-1; VLA-4; VCAM-1; CD2; LFA-3, CD48; CD28; CD80, CD86; IL-12; CD80, CD86; CD48; 接着分子; T細胞活性化

1. We succeeded to establish monoclonal antibodies against mouse CD48 (CD2 ligand), CD80 (B7-1), CD86 (B7-2), CD29 (integrin beta1), CD49a (integrin alpha1), CD49b (alpha2), CD49e (alpha5), CD49f (alpha6), CD40, CD40 ligand, CD95 ligand, that against rat CD86, and those against human CD86, CD95, and CD95 ligand.2. Administration of anti-LFA-1/ICAM-1, anti-VLA-4/VCAM-1, anti-CD2/CD48, or anti-CD80/CD86 mAbs could induce cardiac, bowel, or plancreatic islet allograft tolerance.3. The cardiac allograft tolerance induced by the anti-LFA-1/ICAM-1 treatment was mainly mediated by the inactivation of allogeneic class I-reactive CD8^+ T cells, whereas that induced by anti-CD2/CD48 or anti-CD80/CD86 was mediated by Th2 deviation and/or Th1 inactivation. This suggests divergent mechanisms are responsible for allograft tolerance.4. Lethal GVHD after bone marrow transplantation was prevented by the administration of anti-CD80/CD86 mAbs.5. Administration of anti-LFA-1/ICAM-1 mAbs not only prevented mouse or rat collagen-induced arthritis but also induced resistancy against the subsequent challenge with the same antigen.6. Short-term administration of anti-LFA-1/ICAM-1 mAbs before the onset of insulitis persistently prevented the occurrence of diabetes in NOD mice.7. Administration of anti-CD80/CD86 mAbs prevented the autoantibody production and renal disease in (NZB x NZW) F1 mice.8. Administration of anti-IL-12 mAb not only prevented the experimental autoimmune uveoretinitis (EAU) elicited by IRBP in B10. A mice but also induced resistancy against the subsequent challenge with IRBP.Introduction of IL-12p40 (IL-12 antagonist) gene inhibited the rejection of allogeneic myoblasts.Introduction of IL-12p40 gene along with beta-gal gene inhibited the generation of beta-gal-specific CTL.

1.我们成功地建立了抗小鼠CD 48的单克隆抗体（CD 2配体）、CD 80（B7-1）、CD 86（B7-2）、CD 29（整合素β 1），CD 49 a（整联蛋白α 1），CD 49 b（α 2），CD 49 e（α 5），CD 49 f（α 6），CD 40，CD 40配体，CD 95配体，抗大鼠CD 86的那些，和抗人CD 86，CD 95，和CD 95配体。抗LFA-1/ICAM-1、抗VLA-4/VCAM-1、抗CD 2/CD 48、抗CD 80/CD 86单克隆抗体可诱导心脏、肠道或胰腺胰岛移植耐受.抗LFA-1/ICAM-1处理诱导的心脏移植耐受主要是通过同种异体I类反应性CD 8 ^+ T细胞失活介导的，而抗CD 2/CD 48或抗CD 80/CD 86处理诱导的心脏移植耐受主要是通过Th 2偏移和/或Th 1失活介导的。这表明不同的机制是同种异体移植耐受的原因.通过施用抗CD 80/CD 86单克隆抗体来预防骨髓移植后的致死性GVHD。给予抗LFA-1/ICAM-1单克隆抗体不仅预防小鼠或大鼠胶原诱导的关节炎，而且诱导对随后用相同抗原攻击的抵抗.在胰岛炎发作前短期给予抗LFA-1/ICAM-1单克隆抗体可持续预防NOD小鼠糖尿病的发生.抗CD 80/CD 86单克隆抗体的给药预防了（NZB x NZW）F1小鼠中自身抗体的产生和肾脏疾病。给予抗IL-12 mAb不仅可以预防B10中IRBP引起的实验性自身免疫性葡萄膜视网膜炎（EAU）。IL-12拮抗剂（IL-12 antagonist，IL-12 p40）基因的导入可抑制同种异体成肌细胞的排斥反应，IL-12 p40基因沿着β-gal基因的导入可抑制β-gal特异性CTL的产生。

项目成果

Chavin,K.D.: "Anti-CD2 monoclonal antibodies suppress cytotoxic lymphocyte activity by the generation of Th2 suppressor cells and receptor blockade." J.Immunol.152. 3729-3739 (1994)

Chavin,K.D.：“抗 CD2 单克隆抗体通过 Th2 抑制细胞的生成和受体阻断来抑制细胞毒性淋巴细胞活性。”

Miyake,S.: "beta1 integrin-mediated interaction with cxtracellular matrix proteins regulates cytokine gene expression in synovial fluid cells of rheumatoid arthritis patients." J.Exp.Med.177. 863-868 (1993)

Miyake,S.：“β1 整合素介导的与细胞外基质蛋白的相互作用调节类风湿关节炎患者滑液细胞中的细胞因子基因表达。”

Yagita, H.et al.: "CD95 ligand in graft rejection." Nature. (in press).

Yagita, H.et al.：“移植物排斥中的 CD95 配体。”

Yagita,H.: "Fas-mediated cytotoxicity-A new immunoregulatory and pathogenic function of Th1 CD4^+ T cells." Immunol.Rev.146. in press (1995)

Yagita,H.：“Fas 介导的细胞毒性 - Th1 CD4^ T 细胞的新免疫调节和致病功能。”

Chavin.K.D.: "Auti-CD2 monoclonal antibodies suppress cytotoxic lymphocyte activity bu the gneration of TH2 suppressor cells and receptor blockade." J.Immunol.152(in press). (1994)

Chavin.K.D.：“Auti-CD2 单克隆抗体通过 TH2 抑制细胞的生成和受体阻断来抑制细胞毒性淋巴细胞活性。”