Local immune modulation for beta cell replacement therapy in type 1 diabetes

项目摘要/摘要 该项目的目标是诱导对移植的人的局部免疫耐受。 来自可再生干细胞来源的细胞用于治疗1型糖尿病。我们将测试 我们预防糖尿病患者移植的人干细胞来源的β细胞免疫排斥反应的方法 具有人类免疫系统成分的小鼠。此外，我们还试图解释详细的 该疗法的生物学机制是通过使用胰岛进行体外研究- 反应性人类T细胞。干细胞来源的β-样细胞的生成研究进展 (SBCs)已经提出了为以下目的提供可再生的功能β细胞来源的可能性 移植，有效地克服了人类供体胰岛严重短缺的问题。我们有 生成简化的培养条件，准确高效地生成无限 体外培养的葡萄糖反应性胰岛素表达的β细胞数量。干细胞衍生的贝塔 所产生的细胞已经成功地用于动物的β细胞替代治疗 模特们。通过将细胞工程和生物材料工程相结合来展示负片 免疫调节剂(如程序性死亡-配体1，PD-L1；和肿瘤坏死因子(TNF)- 相关的凋亡诱导配体(TRAIL)，我们将使干细胞来源的β细胞(SBCs)功能化 以对抗移植后的自身免疫。我们方法的一个主要优点是 免疫治疗强烈局限于移植的β细胞，这增加了特异性并避免了 全身免疫治疗的负面副作用。我们假设干细胞来源于 移植PD-L1和/或TRAIL的人假性胰岛对自身免疫具有抵抗力 体内β细胞移植模型中的破坏和增强的植入/存活 用人源化的小鼠进行排斥反应。我们的策略将诱导对β细胞抗原的局部耐受 同时促进SBC移植物的血管化。

PROJECT SUMMARY / ABSTRACT The objective of this project is to induce localized immune tolerance to transplanted human beta cells derived from renewable stem cell sources as a treatment for type 1 diabetes. We will test our approach to prevent immune rejection of grafted human stem cell derived beta cells in diabetic mice with elements of human immune systems. In addition, we seek to explain the detailed biological mechanisms by which the therapy works by conducting in vitro studies using islet- reactive human T cells. Recent advances in the generation of stem cell derived beta-like cells (sBCs) have raised the possibility of providing a renewable source of functional beta cells for transplantation, effectively overcoming the severe shortage of human donor islets. We have generated simplified culture conditions that accurately and efficiently generate unlimited quantities of glucose-responsive insulin-expressing beta cells in vitro. The stem cell derived beta cells generated have already been used successfully for beta cell replacement therapy in animal models. By combining cell engineering with biomaterials engineering to display negative regulators of immunity (e.g. programmed death-ligand 1, PD-L1; and tumor necrosis factor (TNF)- related apoptosis-inducing ligand, TRAIL), we will functionalize stem cell derived beta cells (sBCs) to counter autoimmunity upon transplantation. A major strength of our approach is that the immunotherapy is strongly localized to grafted beta cells, which increases specificity and avoids the negative side effects of systemic immunotherapy. We hypothesize that stem cell derived human pseudo islets transplanted with PD-L1 and/or TRAIL will be resistant to autoimmune destruction and exhibit enhanced engraftment / survival in an in vivo model of beta cell graft rejection using humanized mice. Our strategy will induce localized tolerance to beta cell antigens while simultaneously promoting sBC graft vascularization.