Pathogenic and therapeutic manipulation of the IL-7/IL-7R axis in pancreatic islet transplantation and autoimmunity

1型糖尿病的细胞替代治疗必须考虑控制免疫介导的供体移植物或宿主组织丢失的策略。胰岛移植物排斥反应由自身免疫和同种异体免疫引起。我们发现IL-7/IL-7R途径与自身免疫T细胞介导的胰岛β细胞丢失以及胰岛移植后记忆T细胞的动态平衡增殖有关。我们进一步证明，IL-7可以促进包括自身反应性T细胞在内的T细胞的激活和扩增，并且IL-7在体外可以取消T调节细胞的功能。因此，我们推断，干扰IL-7信号可以改善胰岛移植物的存活率。目前还缺乏一个有用的模型来研究IL-7高表达的影响。我们最近建立了诱导IL-7高表达的小鼠模型，并建立了自身免疫和同种异体免疫的胰岛移植小鼠模型。利用该模型和移植患者的样本，我们将在体内和体外检测IL-7在自身免疫诱导和糖尿病发病后再次暴露于胰岛期间对T细胞的稳态扩张效应。具体地说，我们将：1.确定IL-7的高表达是否以及如何加剧胰岛移植物的丢失和胰岛自身免疫；2.确定成功阻止IL-7介导的β细胞免疫的治疗方法；3.确定人类自身反应性T细胞在稳态增殖下是否容易扩张和发生表型变化。该项目的成功完成将决定IL-7/IL-7R途径是否以及如何针对1型糖尿病，并可能导致用于β细胞移植和1型糖尿病免疫治疗的新的治疗组合。

Cell replacement therapy in type 1 diabetes mellitus must consider strategies to control immune mediated loss of donor graft or host tissue. Islet graft rejection is caused by autoimmunity and alloimmunity. We have shown that the IL-7/IL-7R pathway is relevant to autoimmune T cell mediated islet beta cell loss as well as homeostatic proliferation of memory T cells following islet transplantation. We further showed that IL-7 can favour activation and expansion of T cells, including autoreactive T cells, and that IL-7 can abrogate T regulatory cell function in vitro. Therefore, we reason, that interfering with IL-7 signaling can improve the outcome of islet graft survival. A useful model to study effects of IL-7 hyper-expression is lacking. We recently generated an inducible mouse model of IL-7 hyper-expression and established autoimmune and alloimmune islet transplantation mouse models. Using this model together with samples from patients undergoing transplantation, we will examine in vivo and in vitro IL-7 mediated homeostatic expansion effects on T cells during the induction of autoimmunity and the re-exposure to pancreatic islets after diabetes onset. Specifically, we will: 1. determine if and how IL-7 hyper-expression exacerbates pancreatic islet graft loss and islet autoimmunity; 2. identify therapeutics that successfully hinder IL-7 mediated beta cell immunity; and 3. identify whether autoreactive T cells in man are prone to expand and undergo phenotypic changes under homeostatic proliferation. The successful completion of the project will determine if and how the IL-7/IL-7R pathway should be targeted in type 1 diabetes and will potentially lead to novel therapeutic combinations to be used in beta cell transplantation and type 1 diabetes immunotherapy.