共刺激通路阻断联合抗原特异性Treg细胞诱导异种胰岛细胞移植免疫耐受的研究

异种胰岛移植将会引发强烈的排斥反应，B7/CD28、CD40/CD40L共刺激通路及Treg细胞在异种移植术后排斥反应发生及免疫耐受中起到重要作用，但具体机制尚不明确。我们前期的研究发现通过阻断B7/CD28共刺激通路能够诱导异种移植物的长期存活，其中Treg细胞可能发挥了重要作用。本课题拟通过构建表达猪源性CTLA4Ig和小鼠源性CD40Ig的猪未成熟树突状细胞，并将其输入接受异种胰岛移植的糖尿病小鼠体内，通过特异性地抑制抗原递呈直接途径B7/CD28和间接途径CD40/CD40L共刺激信号，实现对异种移植物的免疫耐受。在免疫耐受模型的基础上，分离抗原特异性Treg细胞，通过体外实验研究抗原特异性Treg细胞对异种抗原的免疫抑制作用；并将Treg细胞输入异种移植动物体内，研究Treg细胞在诱导异种胰岛移植特异性免疫耐受中的作用及其机制。为异种胰岛移植的临床应用提供新的实验及理论基础。

The clinical application of islet xenotransplantation has been limited by a strong T cell-mediated immune response and the requirement for unacceptably high levels of immunosuppression. B7 / CD28, CD40 / CD40L costimulatory pathway and Treg cells play an important role in the presence of immune rejection and early induction of immune tolerance after xenotransplantation respectively. However, the detail mechanism is still obscure. In our previous studies, we found that it is possible to induce immune tolerance in islet xenograft by blocking the B7 / CD28 costimulatory pathway and Treg cells may play an important role in this process. This program intends to construct porcine immature dendritic cells that can express pig-derived CTLA4Ig and mouse-derived CD40Ig specifically and inject them into diabetic mice with islet xenograft to induce immunological tolerance by blockage of B7 / CD28 and CD40 / CD40L costimulatory pathway. Based on the immunotolerance model, antigen-specific Treg cells are isolated to study their effects on lymphocyte proliferation in vitro. Besides, the role and mechanism of antigen-specific Treg cells in inducing specific immune tolerance of islet xenograft will be studied in vivo as well. This is of great significance for the application of xenotransplantation.