Novel Combined Costimulation and CD122 Blockade in Islet Transplantation

 描述(申请人提供)：胰岛移植是一种潜在的治疗1型糖尿病的方法，1型糖尿病是一种影响数百万人的自身免疫性疾病。T细胞介导的排斥反应和钙调神经磷酸酶抑制剂(CNI)免疫抑制的不良反应阻碍了胰岛移植的成功。CNI是一种小分子磷酸酶抑制剂，因其对T细胞有很强的抑制作用而被用于移植，但它们也伴随着许多副作用。1型糖尿病和移植排斥反应是由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)结合，CD28-B7结合提供的共刺激信号，以及通过共享的IL-2/IL-15受体的信号。为了提供T细胞特异性免疫抑制，同时减少CNI治疗相关的发病率，开发了T细胞特异性共刺激阻滞剂belatacept。肾移植后接受贝拉塔塞特治疗的患者与接受CNI治疗的患者相比，移植肾存活率、肾功能、心血管健康和胰岛功能都得到了改善。然而，接受贝拉塔塞特治疗的患者出现了更高的急性T细胞介导的排斥反应的发生率和更严重的分级。最近，我们的实验室证明，当我们联合使用共刺激阻断和抗CD122治疗时，同种异体移植物的存活率有了显著的改善。这不仅延长了小鼠的移植物存活时间，而且在临床前的非人类灵长类肾脏移植模型中也是有效的。这种治疗之所以有效，部分是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，IL15信号已被证明是1型糖尿病自身反应性、胰岛特异性T细胞发展过程中的一条重要途径。因此，我们建议联合使用CD122阻断和共刺激阻断作为预防同种异体和自身反应性T细胞介导的移植胰岛破坏的策略。 我们将首先评估联合治疗在胰岛移植的完全同种异体幼稚和自身免疫模型中的疗效，并与单用共刺激阻断进行比较。然后，我们将使用在我们实验室广泛使用的小鼠OVA TCR转基因系统来表征这种抗CD122和共刺激阻断的新组合诱导长期耐受的细胞机制。拟议的工作将作为申请人培训计划的框架，通过将基础科学研究与移植临床重点相结合，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脏疾病和内分泌疾病。

 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.