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：
10713402
负责人：
Edward Phelps
金额：
$ 7.59万
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/10713402
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.

项目摘要 /摘要该项目的目的是诱导局部免疫耐受性来移植人类beta 源自可再生干细胞源的细胞作为1型糖尿病的治疗方法。我们将测试我们预防糖尿病中接枝的人类干细胞衍生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进行的生物学机制反应性人T细胞。干细胞得出的β样细胞的最新进展（SBC）提高了提供可再生能源beta细胞来源的可能性移植，有效地克服了人类胰岛严重短缺。我们有生成的简化培养条件准确有效地生成无限体外表达葡萄糖反应性胰岛素β细胞的量。干细胞得出的β 已经成功使用的细胞已成功用于动物的β细胞替代疗法型号。通过将细胞工程与生物材料工程相结合以显示负面免疫调节剂（例如编程死亡配体1，PD-L1；和肿瘤坏死因子（TNF） - 相关的凋亡诱导配体，步道），我们将功能化干细胞得出的β细胞（SBC）在移植时应对自身免疫。我们方法的主要优势是免疫疗法强烈局限于移植的β细胞，这会提高特异性并避免全身免疫疗法的负面副作用。我们假设干细胞得出用PD-L1和/或TRAIL移植的人伪胰岛将对自身免疫性有抵抗力在β细胞移植体体内模型中的破坏和展示增强的植入 /生存使用人性化小鼠拒绝。我们的策略将引起对β细胞抗原的局部耐受性同时促进SBC移植血管化。