Islet encapsulation to elicit localized immunosuppression and immune modulation following transplantation

项目摘要/摘要 1型糖尿病(T1D)是一种自身免疫性疾病，导致胰腺b细胞破坏。胰岛渗透 白细胞会产生活性氧(ROS)、促炎细胞因子/趋化因子和T细胞 参与b细胞裂解的效应分子。胰岛移植是治疗T1D的一种很有前途的方法，但 障碍包括免疫介导的排斥反应，免疫抑制对胰岛功能的不良影响，理想 移植部位和同种异体移植物存活率的下降阻碍了人类的可译性。胰岛封装可以 提供免疫保护以保护胰岛功能，防止对胰岛移植物的免疫反应 在移植后。该项目的目标是评估预血运皮下移植的疗效。 用于移植的无装置(DL)部位和增强用于胰岛包膜的新型细胞保护涂层 由单宁酸(TA)的层层氢键组装而成，是一种免疫调节剂 抗氧化剂，聚(N-乙烯基吡咯烷酮)(PVPON)，一种细胞相容的天然和合成聚合物，以及CTLA-4-Ig 抑制同种异体胰岛移植小鼠模型和人源化小鼠模型的T细胞活化。 (PVPON/TA/CTLA-4-Ig)包裹的胰岛在DL部位的移植是有功能的，不会引起 与目前正在临床试验中评估的微囊化装置不同，异物反应可以 在缺乏全局免疫的情况下，降低促炎免疫反应并延迟同种异体移植排斥反应 免疫抑制。我们的主要假设是(PVPON/TA/CTLA-4-Ig)包裹胰岛 能诱导局部免疫抑制并保留胰岛功能 无血管预置装置，无刺激的恶性纤维化。为了解决这一假设， 将在老鼠和人类样本中定义以下独立和相互关联的目的。(1)确定是否 (PVPON/TA/CTLA-4-Ig)包埋可抑制先天和获得性免疫反应 移植后。(2)确定(PVPON/TA/CTLA-4-Ig)封装是否稳定b细胞功能和 减少炎症。从我们的研究中获得的洞察力将确定可以 用于将新的促炎免疫反应抑制剂与我们的适应性 (PVPON/TA/CTLA-4-Ig)涂层进一步延迟胰岛同种异体移植排斥反应，用于未来的人类翻译研究。

Project Summary/Abstract Type 1 diabetes (T1D) is an autoimmune disease resulting in pancreatic b-cell destruction. Islet-infiltrating leukocytes will generate reactive oxygen species (ROS), proinflammatory cytokines/chemokines, and T cell effector molecules involved in b-cell lysis. Islet transplantation is a promising treatment for T1D, but numerous hurdles including immune-mediated rejection, adverse effects of immunosuppression on islet function, ideal sites for transplantation, and declining allograft survival impede human translatability. Islet encapsulation may provide immunoprotection to preserve islet function and prevent immune responses against the islet graft following transplantation. The goal of this project is to assess the efficacy of a pre-vascularized subcutaneous device-less (DL) site for transplantation and to enhance a novel cytoprotective coating for islet encapsulation consisting of a layer-by-layer hydrogen-bonded assembly of tannic acid (TA), an immunomodulatory antioxidant, poly(N-vinylpyrrolidone) (PVPON), a cytocompatible natural and synthetic polymer, and CTLA-4-Ig to inhibit T cell activation in mouse models and humanized mouse models of islet allotransplantation. Transplantation of (PVPON/TA/CTLA-4-Ig)-encapsulated islets in the DL site are functional, does not elicit a foreign body reaction unlike the microencapsulated devices currently being evaluated in clinical trials, can decrease proinflammatory immune responses, and delay allograft rejection in the absence of global immunosuppression. Our overarching hypothesis is that (PVPON/TA/CTLA-4-Ig) encapsulation of islets can elicit localized immunosuppression and preserve islet function following transplantation into a pre-vascularized device-less site without stimulated deleterious fibrosis. To address this hypothesis, the following independent and interrelated aims will be defined in mouse and human samples. (1) Determine if (PVPON/TA/CTLA-4-Ig) encapsulation can suppress proinflammatory innate and adaptive immune responses after transplantation. (2) Determine if (PVPON/TA/CTLA-4-Ig) encapsulation stabilizes b-cell function and decreases inflammation. The insights gained from our studies will identify additional pathways that can be exploited to conjugate novel inhibitors of proinflammatory immune responses to our adaptable (PVPON/TA/CTLA-4-Ig) coatings to further delay islet allograft rejection for future human translational studies.