Novel Combined Costimulation and CD122 Blockade in Islet Transplantation

 描述（由申请人提供）：胰岛移植是1型糖尿病的一种潜在治愈性疗法，1型糖尿病是一种影响数百万人的自身免疫性疾病。胰岛移植的成功受到T细胞介导的排斥反应和基于钙调磷酸酶抑制剂（CNI）的免疫抑制剂的不良反应的毒性的阻碍。CNI是用于移植的小分子磷酸酶抑制剂，其有效的T细胞抑制，但它们伴随着许多副作用。1型糖尿病和移植排斥是由T细胞介导的组织破坏引起的。T细胞需要三种信号来激活：T细胞受体（TCR）接合，由CD 28-B7结合提供的共刺激，以及通过共享的IL-2/IL-15受体的信号传导。为了提供T细胞特异性免疫抑制，但降低与CNI治疗相关的发病率，开发了T细胞特异性共刺激阻断剂贝拉西普。肾移植后接受贝拉西普治疗的患者与接受CNI治疗的患者相比，移植物存活率、肾功能、心血管健康和胰岛功能得到改善。然而，用贝拉西普治疗的患者经历更高比率和更严重等级的急性T细胞介导的排斥。最近，我们的实验室已经证明，当我们结合联合收割机共刺激阻断和抗CD 122治疗时，移植物存活率有了显著改善。这不仅在小鼠中的肾移植物存活，而且在临床前非人灵长类动物肾移植模型中也是有效的。在某种程度上，这种治疗是有效的，因为它减少了可用于排斥反应的抗原特异性T细胞的数量。重要的是，IL 15信号传导已被证明是1型糖尿病中自身反应性胰岛特异性T细胞发育的重要途径。因此，我们建议联合使用CD 122阻断和共刺激阻断作为一种策略，以防止同种异体和自身反应性T细胞介导的移植胰岛的破坏。 我们将首先评估联合治疗在完全同种异体幼稚和自身免疫胰岛移植模型中与单独共刺激阻断相比的疗效。然后，我们将使用在我们实验室中广泛使用的鼠OVA TCR转基因系统来表征这种抗CD 122和共刺激阻断的新型组合的长期耐受诱导的细胞机制。拟议的工作将作为申请人的培训计划的框架，通过将基础科学研究与移植的临床重点相结合，成为一名医生-科学家。这些研究将使用免疫调节疗法解决终末期肾病和内分泌疾病。

 DESCRIPTION (provided by applicant): Islet transplantation is a potentially curative therapy for Type 1 Diabetes, an autoimmune disease that affects millions. The success of islet transplantation is hampered by T cell mediated rejection and toxicities from the untoward effects of calcineurin inhibitor (CNI) based immunosuppression. CNIs are small molecule phosphatase inhibitors used in transplantation for their potent T cell suppression but they are accompanied by many side effects. Type 1 diabetes and transplant rejection result from a T cell mediated destruction of tissue. T cells require three signals for activation: T cell receptor (TCR) engagement, costimulation provided by CD28-B7 binding, and signaling through the shared IL-2/IL-15 receptor. In order to provide T cell specific immunosuppression, but reduce morbidity related to CNI therapy, the T cell specific costimulation blocker Belatacept was developed. Patients treated with Belatacept after kidney transplant enjoy improved graft survival, kidney function, cardiovascular health and islet function compared to those treated with CNIs. However, patients treated with Belatacept experience higher rates and more severe grades of acute T cell mediated rejection. Recently, our lab has demonstrated a dramatic improvement in allograft survival when we combine costimulatory blockade and anti-CD122 treatments. This not only prolongs graft survival in mice but is also effective in a pre-clinical non-human primate kidney transplant model. In part this treatment was effective because it reduced the number of antigen-specific T cells available for rejection. Importantly IL15 signaling has been shown to be an essential pathway in the development of autoreactive, islet specific T cells in Type 1 Diabetes. Thus, we propose using combined CD122 blockade and costimulation blockade as a strategy to prevent both allo- and autoreactive T cell mediated destruction of transplanted islets. We will first evaluate the efficacy of combined therapy in fully allogeneic naïve and autoimmune models of islet transplantation in comparison with costimulation blockade alone. Then we will use the murine OVA TCR transgenic system that has been used extensively in our lab to characterize cellular mechanisms of long-term tolerance induction with this novel combination of anti-CD122 and costimulation blockade. The proposed work will serve as a framework for the applicant's training plan to become a physician-scientist by integrating basic science research with a clinical focus in transplantation. These studies will address end stage kidney disease and endocrine disorders using immunomodulatory therapies.