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Strategies to attenuate the indirect alloimmune response in encapsulated pancreatic islet transplantation

减弱封装胰岛移植中间接同种免疫反应的策略

基本信息

批准号：
10678425
负责人：
Chris Michael Li
金额：
$ 5.27万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10678425
关键词：
Address Alloantigen Allogenic Animal Model Animals Antibodies Antigen Presentation Antigen-Presenting Cells Antigens Attenuated Autoimmune Autoimmune Diseases Beta Cell Binding Biocompatible Materials Biodistribution Biological Biomedical Engineering Blood Glucose CTLA4 gene Cell model Cells Chronic Climacteric Clinic Continuous Glucose Monitor Devices Diagnosis Drug Packaging Encapsulated Environment Equilibrium Face Family suidae Fatty acid glycerol esters Gel Genetic Engineering Glucose Goals Health Hydrogels Hyperglycemia Immune Immune Tolerance Immune response Immunoglobulins Immunosuppression Implant In Vitro Individual Inflammation Inflammatory Insulin Insulin Infusion Systems Insulin-Dependent Diabetes Mellitus Islets of Langerhans Islets of Langerhans Transplantation Kinetics Macrophage Mediating Metabolic Control Methods Mus Organ Donor Oxygen Pathway interactions Patients Permeability Phenotype Physiological Polyethylene Glycols Procedures Protocols documentation Psyche structure Recurrence Refractory Reticular Cell Shapes Signal Transduction Site Stromal Cells Structure of beta Cell of islet T cell response T-Cell Activation T-Lymphocyte Testing Therapeutic Thick Tissue Grafts Transplant Recipients Transplantation Vascularization Vesicle anergy beta cell replacement biomaterial compatibility blood glucose regulation clinically relevant engineered stem cells immunoregulation implantation improved in vivo insulin secretion insulinoma intravenous injection islet lymph nodes mRNA Expression mouse model nanoparticle delivery nanoscale new technology novel paracrine pharmacologic preconditioning protein expression response scaffold targeted delivery translational potential treatment strategy uptake

项目摘要

Project Summary Type 1 diabetes (T1D) is an autoimmune condition that destroys the insulin-producing beta cells within the pancreatic islets of Langerhans. Although the treatment for T1D is aided with new technology like continuous glucose monitoring and automated insulin pumps, exogenous insulin administration is the core management strategy and T1D remains a life-changing and lifelong diagnosis. T1D can be cured by beta cell replacement through pancreatic islet transplantation, however the need for chronic systemic immunosuppression greatly limits the applicability of this procedure. Encapsulation of islets within selectively permeable hydrogels prior to transplantation may eliminate the need for chronic immunosuppression by blocking direct recipient cell and antibody contact with allogeneic islets. The Tomei lab has developed a unique encapsulation method, “conformal coating,” that addresses several considerations of traditional encapsulation methods. Altogether, islet encapsulation has been shown in animal models of T1D to be capable of restoring blood glucose regulation, however recipient innate and adaptive immune cells including macrophages and T cells still initiate a local inflammatory and pericapsular response and limit the long-term efficacy of encapsulated islet transplantation. Given the selective permeability of the hydrogel layer, soluble alloantigens shed by the transplanted islets are likely triggering an indirect allorecognition pathway, where recipient professional antigen-presenting cells scavenge and present alloantigens shed by transplanted islets to alloreactive T cells while simultaneously providing co-stimulatory signal activation. The overall goal of my project is to capitalize on this mechanism by blocking the co-stimulatory pathways required for T cell activation. I hypothesize that combining encapsulated islet transplantation with (1) localized and targeted nanoparticle delivery of biologic co-stimulatory blockers (cytotoxic T lymphocyte antigen 4 immunoglobulin) or (2) co-transplantation with immunomodulatory non- professional antigen presenting cells (that present antigen but do not provide adequate co-stimulation) will induce deletion/anergy of alloreactive T cells and promote tolerance to transplanted islets, thereby improving and prolonging their efficacy in restoring physiologic metabolic control.

项目摘要 1型糖尿病（T1 D）是一种自身免疫性疾病，它破坏了糖尿病患者体内产生胰岛素的β细胞。胰岛虽然T1 D的治疗有新技术的辅助，如连续治疗，血糖监测和自动胰岛素泵，外源性胰岛素给药是核心管理 T1 D仍然是一种改变生活和终身的诊断。T1 D可以通过β细胞替代治疗然而，对慢性全身免疫抑制的需要极大地限制了这一程序的适用性。胰岛在选择性渗透水凝胶内的包封，移植可以通过阻断直接受体细胞而消除对慢性免疫抑制的需要，抗体与同种异体胰岛接触。托梅实验室开发了一种独特的封装方法，涂层”，这解决了传统封装方法的几个考虑因素。总之，小岛在T1 D的动物模型中已经显示包封能够恢复血糖调节，然而，包括巨噬细胞和T细胞在内的受体先天性和适应性免疫细胞仍然启动局部免疫应答。炎症和囊周反应，并限制囊化胰岛移植的长期疗效。考虑到水凝胶层的选择性渗透性，由移植的胰岛脱落的可溶性同种异体抗原被可能触发间接的同种异体识别途径，其中受体专职抗原呈递细胞清除移植胰岛分泌的同种抗原并将其提呈给同种反应性T细胞，同时提供共刺激信号激活。我的项目的总体目标是利用这种机制，阻断T细胞活化所需的共刺激途径。我推测，具有（1）生物共刺激阻断剂局部和靶向纳米颗粒递送的胰岛移植（细胞毒性T淋巴细胞抗原4免疫球蛋白）或（2）与免疫调节非免疫球蛋白共移植，专职抗原呈递细胞（呈递抗原但不提供足够的共刺激）将诱导同种异体反应性T细胞的缺失/无反应性，并促进对移植胰岛的耐受性，从而改善和延长其恢复生理代谢控制的功效。