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

基本信息

批准号：
10596656
负责人：
Edward Phelps
金额：
$ 48.73万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
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/10596656
关键词：
Adamantane Address Animal Model Antigens Apoptosis Architecture Area Attenuated Autoantigens Autoimmunity Automobile Driving Beta Cell Biocompatible Materials Biological Biological Assay Biological Response Modifiers Biology Biomedical Engineering Cadaver Categories Cell Transplantation Cell physiology Cell surface Cells Chemistry Clone Cells Coculture Techniques Collaborations Development Diabetes Mellitus Diabetic mouse Elements Encapsulated Engineering Engraftment Eragrostis Exhibits Gel Generations Genes Genome engineering Glucose Graft Rejection Graft Survival Human Hydrogels Immune Immune Tolerance Immune mediated destruction Immune system Immunity Immunomodulators Immunosuppression Immunosuppressive Agents Immunotherapy Impairment In Vitro Induction of Apoptosis Injectable Insulin Insulin-Dependent Diabetes Mellitus Islet Cell Islets of Langerhans Transplantation Knowledge Ligands Mechanics Microspheres Pathway interactions Patients Performance Polyethylene Glycols Porosity Property Reaction Resistance Source Specificity Structure Surface System T cell response T-Lymphocyte TNF gene Technology Testing Thinness Transgenic Animals Transplantation Vascularization Work anergy antigen-specific T cells autoimmune pathogenesis behavior influence beta cell replacement beta-Cyclodextrins cell killing cell replacement therapy cellular engineering compare effectiveness crosslink cytotoxic CD8 T cells design effector T cell engineered stem cells experimental study graft function human model human stem cells humanized mouse immunoengineering immunoregulation in vitro Model in vivo Model innovation islet novel particle pre-clinical prevent programmed cell death ligand 1 receptor response side effect stem cell biology stem cells synergism therapeutic target

项目摘要

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。