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

描述（由申请人提供）：糖尿病是美国的主要健康问题，有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种方法对大多数患者来说不切实际。睾丸支持细胞（SC）是一种免疫特权细胞，在雄性和雌性糖尿病啮齿动物中跨越免疫屏障移植时，已被证明能够存活并保护共移植的胰岛，而不会产生免疫抑制。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，这种保护的机制尚不清楚，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SC/胰岛共移植对糖尿病的保护作用，还需要更多关于SC免疫保护机制的信息。最近，我们观察到调节性T细胞与SC移植物存活之间的相关性。在这一提议中，我们将验证免疫特权SC通过诱导调节性T细胞来保护共移植胰岛的假设，以及观察到的胰岛移植物存活的变异性是由于SC诱导这些调节性T细胞能力的差异。在目的1中，调节性T细胞在共移植异体胰岛的SC保护中的重要性将通过消耗调节性T细胞和检查对胰岛移植物存活的影响来确定。此外，将测试小鼠在与胰岛移植之前注射从成功的SC/胰岛共移植物中分离的调节性T细胞是否会提高SC提供的保护（减少变异性）。在目标2中，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，这些目标将确定调节性T细胞在共移植异体胰岛的SC保护中的重要性。此外，他们将提供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SC免疫保护胰岛的机制是重要的，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.