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Analysis of tolerance induction using immunosuppresslve dendritic cells in transplantation

移植中免疫抑制树突状细胞耐受诱导的分析

基本信息

批准号：
14370349
负责人：
BECK Yoshifumi
金额：
$ 7.17万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370349/
关键词：
HLA peptide regulatory T cell CD4+CD25+thymus tolerance 臓器移植骨髄移植樹状細胞ビタミンD マウス

项目摘要

CD4+CD25+ regulatory T cells are selected in the thymus to control autoreactive thymic escapees preventing autoimmunity that can not be achieved by negative selection or deletion alone, thus playing an important role in the maintenance of immunological homeostasis. Not only significant in preventing autoimmunity, CD4+CD25+ regulatory T cells have also been shown to be involved in allograft tolerance in organ transplantation. Recent studies suggest that Foxp3, which encodes Scurfin, a member of the forkhead family of transcriptional regulators, is the key regulatory gene for the development of CD4+CD25+ regulatory T cells. We have formerly introduced two lines of HLA class I transgenic mice valuable to elucidate the role of HLA class I molecules in transplantation biology. Here, using a heterotopic cardiac transplantation model, we show that intrathymic inoculation of donor HLA class I derived synthetic peptide results in elevation of Foxp3 level in graft infiltrating lymphocytes and acceptance of the vascularized allograft. In addition, we demonstrate by adoptive transfer experiments that CD4+CD25+ regulatory T cells obtained following intrathymic inoculation of the synthetic peptide effectively induce graft specific tolerance without preconditioning of the recipient or use of additional immunosuppressive drugs. The study provides evidence suggestive of novel therapeutic option with CD4+CD25+ applicable to clinical transplantation.

胸腺中选择了CD4+CD25+调节性T细胞来控制自身反应性胸腺逃逸，从而阻止了单靠阴性选择或缺失不能实现的自身免疫，从而在维持免疫平衡方面发挥了重要作用。CD4+CD25+调节性T细胞不仅在预防自身免疫方面具有重要意义，而且已被证明与器官移植中的同种异体移植耐受有关。最近的研究表明，编码转录调控基因叉头家族成员Scurfin的Foxp3是CD4+CD25+调节性T细胞发育的关键调控基因。我们以前引进了两个HLAI类转基因小鼠品系，对阐明HLAI类分子在移植生物学中的作用有价值。在此，利用异位心脏移植模型，我们发现胸腺内接种供者的HLAI类衍生合成肽可以提高移植物浸润性淋巴细胞中Foxp3的水平，并使带血管的同种异体移植物被接受。此外，我们通过过继转移实验证明，胸腺内接种合成肽后获得的CD4+CD25+调节性T细胞有效地诱导移植物特异性耐受，而无需受体的预适应或使用额外的免疫抑制药物。本研究为临床移植中应用CD4+CD25+细胞提供了新的治疗方案。