Molecular Basis of Immunological Tolerance and Non-Response

免疫耐受和无反应的分子基础

• 批准号: 08044302
• 负责人: SASAZUKI Takehiko
• 金额: $ 5.76万
• 依托单位: Kyushu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for international Scientific Research
• 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-08044302/
• 关键词: TCR; MHC; peptide; HLA-DM; T cell repertoire selection; kinetic stability; 免疫寛容; 単-MHC; ペプチド複合体; トランスジェニックマウス; ノックアウトマウス; 主要組織適合抗原; T細胞受容体; 抗原ペプチド; プロセシング; HLA-DO; 免疫制御; 胸腺内T細胞の選択; TAP; 胸腺T細胞の選択

Immunological tolerance is established by elimination or inactivation of self-reactive T cells through TCR-MHC-peptide interaction in the thymus or periphery. To better understand the molecular mechanism for immunological tolerance, we focused on the generation of MHC/peptide complex and its recognition by TCRs, and obtained several new findings.We revealed that HLA-DM functions as an editor of MHC class II-binding peptides. This would raise the new possibility that the kinetic stability of MHC class II/peptide complex play a important role in tolerance induction. The development and analysis of transgenic-knockout mouse lines expressing a single MHC class IIIpeptide complex brought several new insights into T cells repertoire selection. In addition, we found that organ-specific autoimmunity spontaneously develops in one of such mouse lines, which would argue against the currently prevailing paradigm for MHC class II association with autoimmune diseases.

免疫耐受是通过胸腺或外周中的TCR-MHC-肽相互作用消除或灭活自身反应性T细胞来建立的。为了更好地理解免疫耐受的分子机制，我们重点研究了MHC/肽复合物的产生及其与TCR的识别，并获得了一些新的发现：HLA-DM是MHC II类结合肽的编辑者。这将提出新的可能性，即MHC II类/肽复合物的动力学稳定性在耐受诱导中起重要作用。表达单个MHC III类肽复合物的转基因敲除小鼠系的开发和分析为T细胞库选择带来了一些新的见解。此外，我们发现，器官特异性自身免疫性自发发展在这样的小鼠系之一，这将反对目前流行的模式MHC II类与自身免疫性疾病的关联。

项目成果

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Kropshofer H.：“HLA-DM 编辑 HLA-DR 肽库。”

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Alferink J 等人：“通过外周 T 细胞运输控制新生儿对组织抗原的耐受性。”

Tamai H,et al.: "Association between the DRB1^*08032 histocompatibility antigen and methimazole-induced agranulocytosis in Japanese patients with Graves Disease." Annals of Internal Medicine. 124. 490-494 (1996)

Tamai H 等人：“DRB1^*08032 组织相容性抗原与日本格雷夫斯病患者中甲硫咪唑诱导的粒细胞缺乏症之间的关联。”

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

Hori T.：“日本雪松花粉病和 HLA-DP5”组织抗原。

Ono T,et al.: "Molecular analysis of HLA class I(HLA-A and -B) and HLA class II(HLA-DRB1) genes in Japanese patients with multiple sclerosis(Western type and Asian type)." Tissue Antigens. 52. 539-542 (1998)

Ono T,et al.：“日本多发性硬化症患者（西方型和亚洲型）HLA I 类（HLA-A 和 -B）和 HLA II 类（HLA-DRB1）基因的分子分析”。