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

描述（由申请人提供）：糖尿病是美国的一个主要健康问题，有8.3%的人口受到影响。糖尿病的一种有希望的治疗方法是移植产生胰岛素的胰岛;然而，存在免疫排斥的问题，使得这种手术对大多数患者来说不切实际。睾丸支持细胞（SC）是免疫特权细胞，已被证明在没有免疫抑制的情况下，当跨免疫屏障移植到雄性和雌性糖尿病啮齿动物中时，其存活并保护共移植的胰岛。事实上，男性和女性接受者长期保持正常的血糖水平，生殖正常。然而，这种保护的机制仍然没有得到解决，最近的研究表明，保护能力是可变的。因此，如果我们要改善作为糖尿病治疗的共移植SC/胰岛移植物的保护，需要更多关于SC免疫保护机制的信息。最近，我们观察到调节性T细胞和SC移植物存活之间的相关性。在这个建议中，我们将测试的假设，免疫豁免SC保护共同移植的胰岛诱导调节性T细胞和观察到的变化，胰岛移植物的存活率是由于差异的SC诱导这些调节性T细胞的能力。在目标1中，将通过耗尽调节性T细胞并检查对胰岛移植物存活的影响来确定调节性T细胞在共移植的同种异体胰岛的SC保护中的重要性。此外，将测试在移植胰岛之前注射从成功的SC/胰岛共移植物分离的调节性T细胞的小鼠是否会改善SC提供的保护（降低变异性）。目的2：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，这些目标将确定调节性T细胞在SC保护共移植的同种异体胰岛中的重要性。此外，他们将提供关于SC如何诱导调节性T细胞和保护胰岛移植物的信息。最终理解胰岛SC免疫保护的机制是重要的，因为它有可能通过消除对慢性免疫抑制的需要来改善胰岛移植。

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.