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

1 型糖尿病 β 细胞替代疗法的局部免疫调节

• 批准号: 10632621
• 负责人: Edward Phelps
• 金额: $ 5.06万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10632621
• 关键词: Address; Animal Model; Antigens; Apoptosis; Autoimmunity; Beta Cell; Biocompatible Materials; Biological; Cell Transplantation; Cells; Development; Diabetic mouse; Elements; Engineering; Engraftment; Exhibits; Generations; Glucose; Graft Rejection; Human; Immune; Immune Tolerance; Immune system; Immunity; Immunosuppressive Agents; Immunotherapy; In Vitro; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans Transplantation; Ligands; Resistance; Source; Specificity; T-Lymphocyte; TNF gene; TNFSF10 gene; Testing; Transplantation; Vascularization; Work; autoimmune pathogenesis; beta cell replacement; cell replacement therapy; cellular engineering; human stem cells; humanized mouse; immunoregulation; in vivo Model; innovation; islet; prevent; programmed cell death ligand 1; side effect; stem cells

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.

项目概要/摘要 该项目的目标是诱导对移植的人类β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类干细胞衍生 β 细胞免疫排斥的方法 具有人类免疫系统元素的小鼠。此外，我们试图解释详细的 该疗法通过使用胰岛进行体外研究来发挥作用的生物学机制 反应性人类 T 细胞。干细胞衍生的β样细胞生成的最新进展 （sBC）提出了为功能性β细胞提供可再生来源的可能性 移植，有效克服了人类供体胰岛的严重短缺。我们有 生成简化的培养条件，准确有效地产生无限的 体外表达葡萄糖反应性胰岛素的β细胞的数量。干细胞衍生的β 产生的细胞已成功用于动物的β细胞替代疗法 模型。通过将细胞工程与生物材料工程相结合，显示负电 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)）- 相关的凋亡诱导配体，TRAIL），我们将功能化干细胞衍生的β细胞（sBC） 移植后对抗自身免疫。我们方法的一个主要优势是 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 全身免疫疗法的负面副作用。我们假设干细胞衍生 移植PD-L1和/或TRAIL的人伪胰岛将抵抗自身免疫 在β细胞移植物的体内模型中，破坏并表现出增强的植入/存活 使用人源化小鼠进行排斥反应。我们的策略将诱导对 β 细胞抗原的局部耐受 同时促进 sBC 移植物血管化。