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The role of CD4+CD25+T cells for immunological tolerance induction in organ transplantation

CD4 CD25 T细胞在器官移植免疫耐受诱导中的作用

基本信息

批准号：
16591248
负责人：
BECK Yoshifumi
金额：
$ 2.24万
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 (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16591248/
关键词：
HLA regulatory T cell CD4+CD25+peptide transgenic mouse thymus 移植免疫寛容 HLA CD4+CD25+T細胞マウス心移植移植免疫 CD4CD25 制御性T cell FoxP3

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.

CD4+CD25+调节性T细胞在胸腺中被选择来控制自身反应性胸腺逃逸细胞，防止仅通过负选择或缺失无法实现的自身免疫，从而在维持免疫稳态中发挥重要作用。 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，还被证明参与器官移植中的同种异体移植耐受。最近的研究表明，编码Scurfin（转录调节因子叉头家族成员）的Foxp3是CD4+CD25+调节性T细胞发育的关键调节基因。我们之前引入了两个HLA I 类转基因小鼠品系，对于阐明 HLA I 类分子在移植生物学中的作用很有价值。在这里，使用异位心脏移植模型，我们表明，胸腺内接种供体 HLA I 类衍生的合成肽会导致移植物浸润淋巴细胞中 Foxp3 水平升高并接受带血管的同种异体移植物。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细胞可有效诱导移植物特异性耐受，而无需对受体进行预处理或使用额外的免疫抑制药物。该研究提供了证据表明CD4+CD25+适用于临床移植的新治疗选择。