Novel Costimulation Blockers in Islet Transplantation

描述（由申请人提供）：I型糖尿病是一种进行性自身免疫性疾病，通常使患者依赖外源性胰岛素给药。虽然治疗性胰岛素极大地提高了I型糖尿病患者的预期寿命，但其使用存在显著的发病率和死亡率。产生胰岛素的胰岛的移植提供了一种不依赖于外源性胰岛素给药的恢复正常血糖的潜在方法。同种异体胰岛移植的临床试验在移植后一年的胰岛素依赖性方面显示出巨大的希望;然而，绝大多数患者在移植后五年失去了胰岛素依赖性，最有可能是由于免疫抑制不足和/或毒性。目前的免疫抑制剂，特别是钙调磷酸酶抑制剂（CNI），诱导显著的肾毒性、不良心血管事件，并且可以是致糖尿病的。为了促进胰岛移植治疗的进一步临床应用，需要更有效的免疫抑制剂来保护胰岛移植物。T细胞共刺激通路的拮抗作用是抑制同种异体反应性T细胞应答的有效手段，可替代CNI。用单克隆抗体（mAb）阻断CD 28和CD 40 L通路在临床前模型中显示出巨大的前景。不幸的是，由于Fc介导的交联导致的不希望的副作用，两种mAb在临床上都不可行。为了避免这些问题，我们建议使用新的域抗体（dAb）共刺激阻断剂，不能介导这些不良事件。我们实验室在皮肤移植模型中的数据表明，这些分子在预防移植排斥反应方面具有与现有的共刺激阻断剂CTLA-4 IG和CD 154 mAb相同或更高的功效。本提案的总体目标是评估这些新型dAb在鼠模型中预防同种异体胰岛排斥的潜力。我们将首先评估dAb在以下方面的功效： 与CTLA-4 IG和CD 154 mAb相比，胰岛移植的完全同种异体初始和自身免疫T细胞模型。然后，使用我们实验室广泛使用的OVATCR转基因系统，我们将研究这些dAb诱导移植物长期存活的细胞机制。拟议的研究项目将作为申请人培训计划的框架，将移植耐受性的基础科学研究整合到医生科学家的职业生涯中，其研究兴趣将集中在开发自身免疫性疾病的新疗法。

DESCRIPTION (provided by applicant): Type I diabetes is a progressive autoimmune disease that often renders patients dependent on exogenous insulin administration. While therapeutic insulin has greatly enhanced the life expectancy of Type I diabetics, there is significant morbidit and mortality associated with its use. Transplantation of insulin-producing pancreatic islets offers a potential means of restoring normoglycemia independent of exogenous insulin administration. Clinical trials of alloislet transplantation showed tremendous promise in terms of insulin independence at one year after transplant; however, the great majority of patients lost insulin independence by five years post transplantation, most likely as a result of insufficient and/or toxic immunosuppression. Current immunosuppressive agents, in particular calcineurin inhibitors (CNIs), induce significant renal toxicity, adverse cardiovascular events, and can be diabetogenic. There is a clear need for more effective immunosuppressive agents to preserve islet allografts in order to facilitate the further translation of this therapy to clinical practic. Antagonism of T cell costimulation pathways is an effective means of inhibiting alloreactive T cell responses as an alternative to CNIs. Blockade of the CD28 and CD40L pathways with monoclonal antibodies (mAbs) showed tremendous promise in pre-clinical models. Unfortunately, both mAbs are not clinically viable due to unwanted side effects that are the result of Fc-mediated crosslinking. To circumvent these issues, we propose to use novel domain antibody (dAb) costimulation blockers that cannot mediate these adverse events. Data from our lab in skin transplant models has shown that these molecules possess equal or greater efficacy in preventing graft rejection than the existing costimulation blockade therapeutics CTLA-4 Ig and CD154 mAbs. The overall goal of this proposal is to evaluate the potential of these novel dAbs to prevent alloislet rejection in murine models. We will first evaluate the efficacy of the dAbs in fully allogeneic naive and autoimmune T cell models of islet transplantation compared to CTLA-4 Ig and CD154 mAbs. Then, using the OVA TCR transgenic system that has been extensively utilized in our lab, we will investigate the cellular mechanisms of induction of long-term graft survival by these dAbs. The proposed research project will serve as a framework for the applicant's training plan to integrate basic science research on transplantation tolerance into a career as a physician-scientist whose research interest will focus on developing new therapeutics for autoimmune disease.