Regulatory T cells to improve Sertoli cell protection of transplanted islets.

描述(申请人提供)：糖尿病是美国的一个主要健康问题，8.3%的人口受到影响。一种有希望的治疗糖尿病的方法是移植产生胰岛素的胰岛；然而，免疫排斥的问题使得这一过程对大多数患者来说是不可行的。睾丸支持细胞(Testicular Sertoli Cells，SC)是一种免疫特免性细胞，在没有免疫抑制的情况下，当移植到雄性和雌性糖尿病啮齿动物身上时，它们可以存活并保护联合移植的胰岛。事实上，男性和女性受试者长期保持正常的血糖水平，生殖正常。然而，这种保护的机制仍未解决，最近的研究表明，这种保护能力是可变的。因此，如果我们要提高联合移植的干细胞/胰岛移植物作为糖尿病治疗的保护作用，就需要更多关于干细胞免疫保护机制的信息。最近，我们观察到调节性T细胞与干细胞移植物存活之间的相关性。在这个方案中，我们将检验这样的假设，即免疫特权SC通过诱导调节性T细胞来保护联合移植的胰岛，以及观察到的胰岛移植物存活率的差异是由于SC诱导这些调节性T细胞的能力的差异。在目标1中，调节性T细胞在联合移植的同种异体胰岛干细胞保护中的重要性将通过耗尽调节性T细胞和检测对胰岛移植物存活的影响来确定。此外，小鼠在与胰岛移植之前注射从成功的SC/胰岛联合移植中分离出来的调节性T细胞是否会改善SC提供的保护(减少变异性)，将进行测试。我的目标2，将通过确定SC表达的免疫调节因子在诱导调节性T细胞中的重要性来研究SC诱导调节性T细胞的机制。总的来说，这些目标将决定调节性T细胞在联合移植的同种异体胰岛的干细胞保护中的重要性。此外，他们还将提供有关SC如何诱导调节性T细胞和保护胰岛移植物的信息。最终，了解胰岛干细胞免疫保护的机制是重要的，因为它有可能通过消除慢性免疫抑制来改善胰岛移植。

DESCRIPTION (provided by applicant): Diabetes is a major health concern in the United States, with 8.3% of the population affected. One promising treatment for diabetes is transplantation of insulin-producing pancreatic islets; however, there are issues with immune rejection making this procedure impractical for most patients. Testicular Sertoli cells (SC) are immune privileged cells that have been shown to survive and protect co-grafted islets when transplanted across immunological barriers in male and female diabetic rodents without immunosuppression. In fact, the male and female recipients maintained normal blood glucose levels long-term and were reproductively normal. However, the mechanism for this protection remains unresolved and more recent studies have shown that the protective ability is variable. Thus, if we are to improve the protection of co-transplanted SC/islet grafts as a treatment for diabetes, more information is needed on the mechanism of SC immune protection. Recently, we have observed a correlation between regulatory T cells and SC graft survival. In this proposal, we will test the hypothesis that immune privileged SC protect co-transplanted islets by inducing regulatory T cells and that the observed variability in islet graft survival is due to differences n the ability of SC to induce these regulatory T cells. In aim 1, the importance of regulatory T cell in SC protection of co-transplanted allogeneic islets will be determined by depleting the regulatory T cells and examining the effect on islet graft survival. In addition, whether mice injected with regulatory T cells isolated from successful SC/islet co-grafts prior to transplantatin with islets will improve the protection (decrease the variability) provided by SC will be tested. I aim 2, the mechanism for induction of regulatory T cells by SC will be examined by determining the importance of immunoregulatory factors expressed by SC in the induction of regulatory T cells. Collectively, these aims will determine the importance of regulatory T cells in SC protection of co-transplanted allogeneic islets. Further, they will provide information on how SC induces regulatory T cells and protect islet grafts. Ultimately understanding the mechanism for SC immune protection of islets is important because it has the potential to improve islet transplantation by eliminating the need for chronic immunosuppression.