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

• 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
• 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

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.

项目摘要 I型糖尿病是一种慢性自身免疫性疾病，影响美国300万儿童和成人， 每年花费超过149亿美元。目前，1型糖尿病还没有治愈方法，这是一个关键的问题。 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 1型糖尿病的治疗方法有哪些然而，有四大 同种异体胰岛移植的障碍; i）无效的植入，ii）排斥，iii） 用于控制排斥反应的免疫抑制，和iv）尸体供体胰岛的短缺。因此有 对于克服胰岛移植的这些局限性以用于更广泛的临床实践的策略的显著需要。 该R 01申请旨在开发一种创新且高度转化的免疫调节方案， 克服了胰岛移植的局限性，在缺乏 长期使用免疫抑制剂。 胰岛经门静脉输注入肝是目前临床上唯一的移植途径， 使移植物暴露于血液并引发立即血液介导的炎症反应（IBMIR）。IBMIR是 由血栓形成和炎症反应介导，并导致50-80%胰岛的破坏 移植后即刻。剩下的胰岛随后会被速度较慢但功能强大的 适应性免疫反应严重的早期胰岛丢失需要从2-3个供体移植， 这进一步造成了尸体捐献者的短缺。本提案的目的是 开发强大的，但重点治疗，同时针对直接炎症 反应和适应性免疫反应，以防止早期和晚期移植物丢失。这将是完成 通过产生对血栓形成前，炎症前， 和适应性免疫反应。这些蛋白质将在移植前在胰岛上进行工程改造 用于局部调节血栓形成和炎症反应，以增强植入并实现 无限期的移植物存活，而无需长期使用目前标准的使人衰弱的免疫抑制剂。 这一概念将在三种不同的同种异体胰岛移植环境中进行疗效和 化学糖尿病BALB/c-to-C57 BL/6小鼠，自发糖尿病C57 BL/6-to-NOD小鼠， 和人类胰岛移植到人源化小鼠体内。这些模型将生成与人类环境相关的关键数据。 此外，有效性证明和调节有效结果的免疫机制的阐明 这将加速进一步完善这一免疫调节概念，并最终将其转化为非人类 灵长类动物作为治疗1型糖尿病的临床试验的前奏。