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

项目总结/摘要 本项目的目的是诱导局部免疫耐受移植的人β 来源于可再生干细胞来源的细胞作为1型糖尿病的治疗。我们将测试 我们在糖尿病患者中预防移植的人干细胞衍生的β细胞的免疫排斥的方法 具有人类免疫系统的小鼠此外，我们还将详细解释 通过使用胰岛细胞进行体外研究， 反应性人类T细胞干细胞源性β细胞的研究进展 （sBC）已经提高了提供功能性β细胞的可再生来源的可能性， 移植，有效地克服了人类供体胰岛的严重短缺。我们有 产生的简化的培养条件，准确和有效地产生无限的 量的葡萄糖响应性胰岛素表达β细胞。干细胞衍生的β 产生的细胞已经成功地用于动物的β细胞替代疗法， 模型将细胞工程与生物材料工程相结合， 免疫调节剂（例如程序性死亡配体1，PD-L1;和肿瘤坏死因子（TNF））， 相关凋亡诱导配体，TRAIL），我们将功能化干细胞衍生的β细胞（sBC） 以对抗移植后的自身免疫。我们的方法的一个主要优点是， 免疫疗法强烈定位于移植的β细胞，这增加了特异性并避免了免疫缺陷。 全身免疫疗法的副作用我们假设干细胞衍生 用PD-L1和/或TRAIL移植的人假胰岛将抵抗自身免疫性 破坏并在β细胞移植物的体内模型中表现出增强的植入/存活 使用人源化小鼠的排斥反应。我们的策略将诱导局部耐受β细胞抗原 同时促进sBC移植物血管化。

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.