Islet encapsulation to elicit localized immunosuppression and immune modulation following transplantation

移植后胰岛封装引发局部免疫抑制和免疫调节

基本信息

批准号：
10667778
负责人：
Eugenia Kharlampieva
金额：
$ 58.96万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
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：
2023-09-15 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10667778
关键词：
Address Adverse effects Alginates Allografting Antioxidants Area Autoimmune Diseases B-Lymphocytes Beta Cell Biocompatible Materials Biological Assay CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CTLA4-Ig Cell physiology Clinical Clinical Trials Complement Cytolysis Cytoprotection Dendritic Cells Devices Diabetes Mellitus Encapsulated Ensure Fibrosis Flow Cytometry Foreign-Body Reaction Future Goals Graft Rejection Human Hydrogen Bonding Immune Immune mediated destruction Immune response Immune system Immunofluorescence Immunologic Immunosuppression Inflammation Inflammatory Inflammatory Response Innate Immune Response Insulin Insulin-Dependent Diabetes Mellitus Interferon alpha Islets of Langerhans Transplantation Leucocytic infiltrate Macrophage Mediating Metabolic Mus Natural Killer Cells Pathway interactions Patients Polymers Predisposition Reactive Oxygen Species Research Role Sampling Site Skin Structure of beta Cell of islet T cell response T-Cell Activation Tannic Acid Technology Transplantation Vascularization adaptive immune response allograft rejection allotransplant arm chemokine clinical application comparative efficacy cytokine cytotoxic CD8 T cells diabetic effector T cell efficacy evaluation euglycemia humanized mouse immune activation immunoregulation inhibitor insight insulin secretion islet islet allograft islet amyloid polypeptide mouse model neutrophil novel preservation prevent response scaffold single-cell RNA sequencing subcutaneous transcriptomics translational study

项目摘要

Project Summary/Abstract Type 1 diabetes (T1D) is an autoimmune disease resulting in pancreatic b-cell destruction. Islet-infiltrating leukocytes will generate reactive oxygen species (ROS), proinflammatory cytokines/chemokines, and T cell effector molecules involved in b-cell lysis. Islet transplantation is a promising treatment for T1D, but numerous hurdles including immune-mediated rejection, adverse effects of immunosuppression on islet function, ideal sites for transplantation, and declining allograft survival impede human translatability. Islet encapsulation may provide immunoprotection to preserve islet function and prevent immune responses against the islet graft following transplantation. The goal of this project is to assess the efficacy of a pre-vascularized subcutaneous device-less (DL) site for transplantation and to enhance a novel cytoprotective coating for islet encapsulation consisting of a layer-by-layer hydrogen-bonded assembly of tannic acid (TA), an immunomodulatory antioxidant, poly(N-vinylpyrrolidone) (PVPON), a cytocompatible natural and synthetic polymer, and CTLA-4-Ig to inhibit T cell activation in mouse models and humanized mouse models of islet allotransplantation. Transplantation of (PVPON/TA/CTLA-4-Ig)-encapsulated islets in the DL site are functional, does not elicit a foreign body reaction unlike the microencapsulated devices currently being evaluated in clinical trials, can decrease proinflammatory immune responses, and delay allograft rejection in the absence of global immunosuppression. Our overarching hypothesis is that (PVPON/TA/CTLA-4-Ig) encapsulation of islets can elicit localized immunosuppression and preserve islet function following transplantation into a pre-vascularized device-less site without stimulated deleterious fibrosis. To address this hypothesis, the following independent and interrelated aims will be defined in mouse and human samples. (1) Determine if (PVPON/TA/CTLA-4-Ig) encapsulation can suppress proinflammatory innate and adaptive immune responses after transplantation. (2) Determine if (PVPON/TA/CTLA-4-Ig) encapsulation stabilizes b-cell function and decreases inflammation. The insights gained from our studies will identify additional pathways that can be exploited to conjugate novel inhibitors of proinflammatory immune responses to our adaptable (PVPON/TA/CTLA-4-Ig) coatings to further delay islet allograft rejection for future human translational studies.

项目概要/摘要 1 型糖尿病 (T1D) 是一种导致胰腺 B 细胞破坏的自身免疫性疾病。胰岛浸润白细胞会产生活性氧 (ROS)、促炎细胞因子/趋化因子和 T 细胞参与 b 细胞裂解的效应分子。胰岛移植是治疗 T1D 的一种有前景的方法，但障碍包括免疫介导的排斥反应、免疫抑制对胰岛功能的不利影响、理想的移植部位的限制和同种异体移植物存活率的下降阻碍了人类的可移植性。胰岛封装可能提供免疫保护以保护胰岛功能并防止针对胰岛移植物的免疫反应移植后。该项目的目标是评估预血管化皮下注射的功效用于移植的无装置（DL）位点并增强用于胰岛封装的新型细胞保护涂层由单宁酸 (TA) 的逐层氢键组装组成，单宁酸是一种免疫调节剂抗氧化剂、聚（N-乙烯基吡咯烷酮）（PVPON）、一种细胞相容性天然和合成聚合物以及 CTLA-4-Ig 抑制胰岛同种移植小鼠模型和人源化小鼠模型中的 T 细胞活化。在 DL 位点移植 (PVPON/TA/CTLA-4-Ig) 封装的胰岛是有功能的，不会引起与目前正在临床试验中评估的微胶囊装置不同，异物反应可以减少促炎性免疫反应，并在缺乏整体性的情况下延迟同种异体移植排斥免疫抑制。我们的首要假设是 (PVPON/TA/CTLA-4-Ig) 胰岛封装可以引起局部免疫抑制并在移植到胰岛后保留胰岛功能预血管化无装置部位，不会刺激有害纤维化。为了解决这个假设，将在小鼠和人类样本中定义以下独立且相互关联的目标。 (1) 判断是否 (PVPON/TA/CTLA-4-Ig) 封装可抑制促炎性先天性和适应性免疫反应移植后。 (2) 确定 (PVPON/TA/CTLA-4-Ig) 封装是否稳定 b 细胞功能，以及减少炎症。从我们的研究中获得的见解将确定可以的其他途径用于将促炎性免疫反应的新型抑制剂与我们的适应性结合起来 (PVPON/TA/CTLA-4-Ig) 涂层可进一步延迟胰岛同种异体移植排斥，用于未来的人类转化研究。