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治疗。虽然治疗性胰岛素大大提高了I型糖尿病患者的预期寿命，但与使用胰岛素相关的发病率和死亡率也很高。产生胰岛素的胰岛移植提供了一种独立于外源性胰岛素管理恢复正常血糖的潜在手段。同种异体胰岛移植的临床试验显示，在移植后一年内胰岛素独立性方面有巨大的希望；然而，绝大多数患者在移植后5年内失去胰岛素独立性，很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（CNIs），会引起严重的肾毒性、不良心血管事件，并可能导致糖尿病。显然需要更有效的免疫抑制剂来保护同种异体胰岛移植，以促进这种疗法进一步转化为临床实践。T细胞共刺激途径的拮抗是抑制同种异体反应性T细胞反应的有效手段，可以替代cni。单克隆抗体（mab）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，由于fc介导交联的不良副作用，这两种单克隆抗体在临床上都不可行。为了避免这些问题，我们建议使用不能介导这些不良事件的新型结构域抗体（dAb）共刺激阻滞剂。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方面具有与现有的共刺激阻断疗法CTLA-4 Ig和CD154 mab相同或更高的功效。本提案的总体目标是评估这些新型dAbs在小鼠模型中预防同种异体排斥反应的潜力。我们将首先评估dAbs的疗效

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.