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.

项目摘要/摘要 1型糖尿病（T1D）是一种自身免疫性疾病，导致胰腺B细胞破坏。胰岛浸润白细胞将产生活性氧（ROS），促炎细胞因子/趋化因子和T细胞涉及B细胞裂解的效应分子。胰岛移植是T1D的一种有前途的治疗方法，但许多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，理想的障碍，理想移植和同种异体生存下降的位置阻碍了人类的转换性。胰岛封装可能提供免疫保护以保存胰岛功能并防止针对胰岛移植物的免疫反应移植后。该项目的目的是评估血管前皮下的功效用于移植的无设备（DL）位点，并增强新型的细胞保护涂层用于胰岛封装由单层氢键组成的单宁酸（TA），一种免疫调节的组成抗氧化剂，聚（N-乙烯基吡咯烷酮）（PVPON），一种细胞相容的天然和合成聚合物，以及CTLA-4-Eg 抑制小鼠模型和胰岛同种异体移植小鼠模型中的T细胞活化。 DL位点中包含的胰岛的移植（PVPON/TA/CTLA-4-4-Ig）功能性，不会引起A 与当前在临床试验中评估的微封装设备不同，外国身体反应可以减少促炎性免疫反应，并在没有全球的情况下延迟同种异体移植的排斥反应免疫抑制。我们的总体假设是（PVPON/TA/CTLA-4-4-Ig）胰岛封装可以在移植到A后引起局部免疫抑制和保存胰岛功能没有刺激有害纤维化的无动用部位的无动用部位。为了解决这一假设，遵循独立和相互关联的目标将在小鼠和人类样品中定义。（1）确定是否（PVPON/TA/CTLA-4-IG）封装可以抑制促炎的先天和适应性免疫反应移植后。（2）确定（PVPON/TA/CTLA-4-ig）是否稳定B细胞函数和减少炎症。从我们的研究中获得的见解将确定可能是利用促进促炎性免疫反应的新型抑制剂对我们适应性的抑制剂（PVPON/TA/CTLA-4-IG）涂层，以进一步延迟同种异体移植的抑制，以进行未来的人类翻译研究。