Analyses 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: 08457109
• 负责人: YAGITA Hideo
• 金额: $ 5.06万
• 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 Scientific Research (B)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08457109/
• 关键词: tolerance; transplantation; autoimmune disease; immune privilege; Th1; Th2; costimulation; FasL; CD80; CD86; CD27; OX40; Fasリガンド; IL-12; LFA-1; ICAM-1; CD40; CD95

1, The cardiac allograft tolerance induced by the anti-LFA-l/ICAM-1 treatment was mainly mediated by the inactivation of allogeneic classi-reactive CD8^+ T cells, whereas that induced by anti-CD/fCD48 or anti-CD8O/CD86 was mediated by Th2 deviation and/or Th1 inactivation. This suggests divergent mechanisms are responsible for allograft tolerance.2, The cardiac allograft tolerance induced by the anti-LFA-l/ICAM-l or anti-CD8OICD86 treatment was so stable that it could not be broken by subsequent challenge with donor-type cells transduced with IL-2, IL-12, or CD8O genes.3, Lethal GVHD after bone marrow transplantation was prevented by the administration of anti-CDBO/CD86 mAbs.4, Short-term administration of anti-LFA-1/ICAM-l mAbs before the onset of insulitis persistently prevented the occurrence of diabetes in NOD mice.5. Administration of anti-IL-12 mAb not only prevented the experimental autoimmune uveoretinitis (EAU) elicited by IRBP in BlO.A mice but also induced resistancy against … More the subsequent challenge with IRBP.6. Introduction of LL-12p40 (IL-12 antagonist) gene inhibited the rejection of allogeneic myoblasts.7. We characterized the expression and function of human and murine FasL by generating mAbs.8, In a murine model of lethal acute GVHD, administration of anti-FasL and anti-TNFalpha mAbs led to a chimeric state of tolerance.9, We revealed that CD8O/CD86-independent rejection of allogeneic hepatocytes is mediated by FsaIFasL system.10, We revealed that FasL expressed on corneal endothelium critically contributes to corneal allograft survival.11, While FasL-transfected cells underwent repid rejection by neutorphils, co-transfection of IL-b or TGF-beta inhibited the neutrophil-mediated rejection.12, We established mAbs against mouse CD7O, OX4OL, CD3OL, and 4-1BBL and characterized the expression and function of these costimulatory molecules.13, We established mAbs against rat CD8O, CD86, and OX4OL and characterized the expression and function of these costimulatory molecules. Less

1、抗LFA-L/ICAM-1诱导的心脏移植耐受主要由同种异体类反应性CD8~+T细胞失活介导，而抗CD/fCD48或抗CD80/CD86诱导的耐受主要由Th2偏移和/或Th1失活介导。提示异基因移植耐受机制不同。2、抗LFA-L/ICAM-L或抗CD8OICD86单抗诱导的心脏移植耐受非常稳定，不能通过后续的IL-2、IL-12或CD80基因转导的供体型细胞攻击而被打破。3、骨髓移植后致死性移植物抗宿主病可通过给予抗CDBO/CD86单抗预防。4、在糖尿病小鼠发病前短期给予抗LFA-1/ICAM-L单抗持续预防糖尿病的发生。应用抗IL-12单抗不仅可预防IRBP诱导的小鼠实验性自身免疫性葡萄膜视网膜炎(EAU)，而且可诱导对…的抵抗IRBP.6的更多后续挑战。IL-12拮抗剂IL-12p40基因的导入抑制了同种异体成肌细胞的排斥反应。8、在致死性急性移植物抗宿主病小鼠模型中，抗FasL和抗肿瘤坏死因子αmAbs的应用导致了一种嵌合的耐受状态。9、我们揭示了CD8O/CD86非依赖的同种异体肝细胞排斥反应是由FsaIFasL系统介导的。10、我们揭示了在角膜内皮细胞上表达的FasL对角膜移植物的存活起着至关重要的作用。11.而FasL转基因细胞通过中性粒细胞发生快速排斥反应，IL-b或转化生长因子-β的联合感染抑制了中性粒细胞介导的排斥反应。12、我们建立了针对小鼠CD7O、OX4OL、CD3OL、CD3OL的mAbs13、我们建立了抗大鼠CD8O、CD86和OX4OL的单抗，并对这些共刺激分子的表达和功能进行了研究。较少

项目成果

Maeda, K., Sato, T., Azuma, M., Yagita, H., and Okumura, K.: "Characterization of rat CD80 and CD86 by molecular cloning and mAb." Int.Immunol.9. 993-1000 (1997)

Maeda, K.、Sato, T.、Azuma, M.、Yagita, H. 和 Okumura, K.：“通过分子克隆和 mAb 表征大鼠 CD80 和 CD86。”

Nakano,H.: "Differential regulation of IKKα and IKKβ by two upstream kinases,NIK and MEKK1." Proc.Natl.Acad.Sci.USA. 95. 3537-2542 (1998)

Nakano, H.：“两种上游激酶 NIK 和 MEKK1 对 IKKα 和 IKKβ 的差异调节。Proc.Natl.Acad.Sci.USA 95. 3537-2542 (1998)。

Oshima,H.: "Characterization of murine CD70 by molecular cloning and mAb." Int.Immunol.10. 517-526 (1998)

Oshima,H.：“通过分子克隆和 mAb 表征鼠 CD70。”

Kato,K.: "Local production of the p40 subunit of interleukin 12 suppresses T-helperl-mediated immune responses and prevents allogeneic myoblast rejection." Proc.Natl.Acad.Sci.USA. 93. 9085-9089 (1996)

Kato,K.：“白细胞介素 12 的 p40 亚基的局部产生可抑制 T-helper1 介导的免疫反应，并防止同种异体成肌细胞排斥。”

Saito,K.: "Effect of CD80 and CD86 blockade and anti-IL-12 treatment on mouse acute graft-versus-host disease." Eur.J.Immunol.26. 3098-3106 (1996)

Saito,K.：“CD80 和 CD86 阻断以及抗 IL-12 治疗对小鼠急性移植物抗宿主病的影响。”