Strategies to attenuate the indirect alloimmune response in encapsulated pancreatic islet transplantation

项目摘要 1型糖尿病(T1D)是一种自身免疫性疾病，它会破坏体内产生胰岛素的β细胞 朗格汉斯的胰岛。虽然对T1D的治疗是通过连续等新技术进行的 血糖监测和自动胰岛素泵，外源性胰岛素注射是核心管理 战略和T1D仍然是一个改变人生的终生诊断。T1D可通过贝塔细胞置换治愈 然而，通过胰岛移植，慢性全身免疫抑制的需要在很大程度上限制了 这一程序的适用性。在选择性渗透性水凝胶中包裹胰岛 移植可以通过阻断直接受体细胞和 抗体与同种异体胰岛接触。Tomei实验室开发了一种独特的封装方法--“保形” 涂层“，它解决了传统封装方法的几个考虑因素。总而言之，小岛 胶囊在T1D动物模型中已被证明能够恢复血糖调节， 然而，接受者包括巨噬细胞和T细胞在内的先天和获得性免疫细胞仍然启动局部 炎症反应和包膜周围反应，限制了囊化胰岛移植的长期疗效。 由于水凝胶层的选择性渗透性，移植的胰岛脱落的可溶性同种异体抗原是 可能触发间接同种异体识别途径，其中受体专业抗原提呈细胞 同时清除移植胰岛对同种异体反应性T细胞的同种异体抗原 提供共刺激信号激活。我项目的总体目标是通过以下方式利用这一机制 阻断T细胞激活所需的共刺激通路。我假设组合封装了 应用(1)生物共刺激阻滞剂的局部和靶向纳米颗粒的胰岛移植 细胞毒性T淋巴细胞抗原4免疫球蛋白)或(2)与免疫调节性非 专业的抗原提呈细胞(提呈抗原，但不能提供充分的协同刺激)将诱导 同种异体反应性T细胞的缺失/无能，并促进对移植胰岛的耐受性，从而改善和 延长它们在恢复生理代谢控制方面的效力。

Project Summary Type 1 diabetes (T1D) is an autoimmune condition that destroys the insulin-producing beta cells within the pancreatic islets of Langerhans. Although the treatment for T1D is aided with new technology like continuous glucose monitoring and automated insulin pumps, exogenous insulin administration is the core management strategy and T1D remains a life-changing and lifelong diagnosis. T1D can be cured by beta cell replacement through pancreatic islet transplantation, however the need for chronic systemic immunosuppression greatly limits the applicability of this procedure. Encapsulation of islets within selectively permeable hydrogels prior to transplantation may eliminate the need for chronic immunosuppression by blocking direct recipient cell and antibody contact with allogeneic islets. The Tomei lab has developed a unique encapsulation method, “conformal coating,” that addresses several considerations of traditional encapsulation methods. Altogether, islet encapsulation has been shown in animal models of T1D to be capable of restoring blood glucose regulation, however recipient innate and adaptive immune cells including macrophages and T cells still initiate a local inflammatory and pericapsular response and limit the long-term efficacy of encapsulated islet transplantation. Given the selective permeability of the hydrogel layer, soluble alloantigens shed by the transplanted islets are likely triggering an indirect allorecognition pathway, where recipient professional antigen-presenting cells scavenge and present alloantigens shed by transplanted islets to alloreactive T cells while simultaneously providing co-stimulatory signal activation. The overall goal of my project is to capitalize on this mechanism by blocking the co-stimulatory pathways required for T cell activation. I hypothesize that combining encapsulated islet transplantation with (1) localized and targeted nanoparticle delivery of biologic co-stimulatory blockers (cytotoxic T lymphocyte antigen 4 immunoglobulin) or (2) co-transplantation with immunomodulatory non- professional antigen presenting cells (that present antigen but do not provide adequate co-stimulation) will induce deletion/anergy of alloreactive T cells and promote tolerance to transplanted islets, thereby improving and prolonging their efficacy in restoring physiologic metabolic control.