Novel Costimulation Blockers in Islet Transplantation

描述(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注射。虽然治疗性胰岛素极大地延长了I型糖尿病患者的预期寿命，但它的使用也有显著的发病率和死亡率。产生胰岛素的胰岛移植提供了一种潜在的恢复正常血糖的方法，不依赖于外源性胰岛素注射。同种异体胰岛移植的临床试验显示，在移植后一年的胰岛素独立性方面有很大的希望；然而，绝大多数患者在移植后五年失去胰岛素独立性，很可能是由于免疫抑制不足和/或有毒。目前的免疫抑制剂，特别是钙调神经磷酸酶抑制剂(CNI)，会引起严重的肾脏毒性、不良心血管事件，并可导致糖尿病。显然，需要更有效的免疫抑制剂来保存同种异体胰岛移植物，以促进这种治疗方法的进一步临床应用。拮抗T细胞共刺激通路是抑制同种异体反应性T细胞反应的有效手段，可替代CNI。用单抗阻断CD28和CD40L通路在临床前模型中显示出巨大的前景。不幸的是，这两种单抗在临床上都不可行，因为FC介导的交联会产生不良的副作用。为了避免这些问题，我们建议使用新型的区域抗体(DAB)共刺激阻滞剂，它不能调节这些不良事件。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与现有的共刺激阻断疗法CTLA-4 Ig和CD154单抗具有同等或更高的疗效。这项建议的总体目标是评估这些新的DAB在小鼠模型中预防同种异体胰岛排斥反应的潜力。我们将首先评估DABS的效果。 胰岛移植的全异基因幼稚和自身免疫T细胞模型与CTLA-4Ig和CD154单抗的比较然后，利用我们实验室广泛使用的OVA TCR转基因系统，我们将研究这些Dabs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者培训计划的框架，将移植耐受的基础科学研究纳入内科科学家的职业生涯，其研究兴趣将集中在开发治疗自身免疫性疾病的新疗法上。

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.