A novel immunomodulatory approach to overcome innate and adaptiveimmune barriers to islet transplantation

一种克服胰岛移植先天性和适应性免疫障碍的新型免疫调节方法

基本信息

批准号：
10289717
负责人：
Haval Shirwan
金额：
$ 39.43万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-11-05 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10289717
关键词：
Adult Adverse effects Affect Allogenic Antigens Apoptosis Autoantigens Autoimmune Autoimmune Diseases Biological Response Modifiers Blood C57BL/6 Mouse CD47 gene Cadaver Cells Cessation of life Chemicals Child Chronic Clinical Clinical Treatment Clinical Trials Coagulation Process Complement Data Development Diabetic mouse Eating Engineering Engraftment FOXP3 gene Goals Graft Rejection Graft Survival Health Care Costs Homologous Transplantation Human IL2RA gene Immune Immunity Immunosuppression Inbred BALB C Mice Inbred NOD Mice Inflammatory Inflammatory Response Infusion procedures Innate Immune Response Insulin Insulin-Dependent Diabetes Mellitus Islets of Langerhans Islets of Langerhans Transplantation Leucocytic infiltrate Liver Mediating Medical Methods Modeling Natural Immunity Outcome Pancreas Pathway interactions Phagocytes Phagocytosis Platelet Activation Play Population Portal vein structure Prevention Proteins Prothrombin Protocols documentation Reaction Recombinant Proteins Regimen Regulatory T-Lymphocyte Role Route SHPS-1 protein Signal Transduction Stimulus Streptavidin Structure of beta Cell of islet Surface Testing Therapeutic Thrombin Thrombomodulin Thromboplastin Translating Translations Transplantation Treatment Protocols Work adaptive immune response adaptive immunity allograft rejection blood glucose regulation chronic autoimmune disease clinical practice design diabetic effector T cell efficacy evaluation graft function humanized mouse immune clearance immunoreaction immunoregulation innovation islet monocyte mouse model neutrophil new technology nonhuman primate novel novel strategies post-transplant prevent response standard care thrombotic transplant model

项目摘要

PROJECT SUMMARY Type I diabetes is a chronic autoimmune that affects 3 million children and adults in the US with healthcare costs exceeding $14.9 billion annually. Currently, there is no cure for type 1 diabetes, representing a critical unmet medical need. Transplantation of allogeneic islets is a reliable method of achieving durable glucose homeostasis and preventing the devastating complications of type 1 diabetes. However, there are four major barriers to allogeneic islet transplantation; i) ineffective engraftment, ii) rejection, iii) adverse effects of immunosuppression used to control rejection, and iv) shortage of cadaveric donor islets. Therefore, there is a significant need for strategies that overcome these limitations of islet transplantation for a broader clinical practice. This R01 application aims to develop an innovative and highly translational immunomodulatory protocol to overcome the limitations of islet transplantation for sustained long-term graft survival in the absence of chronic use of immunosuppression. Infusion of islets into the liver via portal vein, the only route of transplantation in clinical use, instantly exposes the graft to blood and initiates an immediate blood-mediated inflammatory reaction (IBMIR). IBMIR is mediated by thrombotic and inflammatory reactions and is responsible for the destruction of 50-80% islets immediate post-transplantation. The remaining islets are then subject to rejection by the slower, but potent adaptive immune responses. Significant early islet loss requires transplantation from 2-3 donors per recipients, which further contribute to the shortage of cadaveric donors. The goal of this proposal is to develop powerful, yet focused therapies to simultaneously target the immediate inflammatory reactions and adaptive immune response to prevent early and late graft loss. This will be accomplished by generating novel recombinant proteins with robust inhibitory functions on prothrombotic, proinflammatory, and adaptive immune reactions. These proteins will be engineered on pancreatic islets before transplantation for localized modulation of thrombotic and inflammatory responses to enhance engraftment and achieve indefinite graft survival without the chronic use of debilitating immunosuppression that is currently standard. This concept will be tested in three different allogeneic islet transplantation settings for efficacy and mechanisms; chemically diabetic BALB/c-to-C57BL/6 mice, spontaneously diabetic C57BL/6-to-NOD mice, and human islets into humanized mice. These models will generate critical data relevant to the human setting. Furthermore, proof-of-efficacy and the elucidation of the immune mechanisms regulating effective outcomes will expedite further refinement of this immunomodulatory concept and its eventual translation to nonhuman primates as a prelude to clinical trials for the treatment of type 1 diabetes.

项目概要 I 型糖尿病是一种慢性自身免疫性疾病，影响着美国 300 万接受医疗保健的儿童和成人每年的成本超过 149 亿美元。目前，1 型糖尿病尚无治愈方法，这是一个严重的问题未满足的医疗需求。同种异体胰岛移植是获得持久葡萄糖的可靠方法体内平衡并预防 1 型糖尿病的破坏性并发症。不过，主要有四个同种异体胰岛移植的障碍； i) 无效植入，ii) 排斥反应，iii) 不良反应用于控制排斥反应的免疫抑制，以及 iv) 尸体供体胰岛的短缺。因此，有一个迫切需要克服胰岛移植的这些局限性以进行更广泛的临床实践的策略。该 R01 应用旨在开发一种创新且高度转化的免疫调节方案克服胰岛移植的局限性，在缺乏胰岛细胞的情况下实现移植物的长期持续存活长期使用免疫抑制剂。通过门静脉将胰岛立即输注至肝脏，这是临床使用的唯一移植途径将移植物暴露于血液并立即引发血液介导的炎症反应（IBMIR）。 IBMIR 是由血栓和炎症反应介导，导致 50-80% 的胰岛遭到破坏移植后立即进行。然后，剩余的胰岛会受到速度较慢但有效的胰岛的排斥。适应性免疫反应。显着的早期胰岛损失需要每个 2-3 名捐献者进行移植受者，这进一步加剧了尸体捐赠者的短缺。该提案的目标是开发强大而有针对性的疗法，同时针对即时炎症反应和适应性免疫反应，以防止早期和晚期移植物丢失。这将实现通过生成对促血栓形成、促炎症、和适应性免疫反应。这些蛋白质将在移植前在胰岛上进行改造用于局部调节血栓和炎症反应，以增强植入并实现移植物无限期存活，无需长期使用目前标准的使人衰弱的免疫抑制。这一概念将在三种不同的同种异体胰岛移植环境中进行测试，以验证其功效和作用机制；化学性糖尿病 BALB/c-to-C57BL/6 小鼠，自发性糖尿病 C57BL/6-to-NOD 小鼠，和人类胰岛转化为人源化小鼠。这些模型将生成与人类环境相关的关键数据。此外，功效证明和调节有效结果的免疫机制的阐明将加速这一免疫调节概念的进一步完善及其最终转化为非人类灵长类动物作为治疗 1 型糖尿病临床试验的前奏。