Complement-Mediated Exosome Function in Transplantation

移植中补体介导的外泌体功能

基本信息

批准号：
10563092
负责人：
Nicholas Chun
金额：
$ 56.5万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-22 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10563092
关键词：
Acute Allografting Antigen-Presenting Cells Binding Biology Blocking Antibodies C3bi Cells Cellular Immunity Chronic Clinical Trials Complement Complement 3b Complement 4b Complement Activation Complement Degradation Complement Receptor Data Dendritic Cells Deposition Development Disease Dual-role transvestism Frequencies Gene Expression Generations Genetic Graft Rejection Graft Survival Health Heart failure Human ITGAX gene Immune Immune response Immunity In Vitro Injury Integrin alphaXbeta2 Knock-out Lead Ligation Link Major Histocompatibility Complex Mannose Binding Lectin Mediating Mediator of activation protein Modeling Morbidity - disease rate Opsonin Organ Donor Outcome Pathogenicity Pathway interactions Patients Peptides Pharmacology Plasma Process Publishing Reporting Research Resistance Role Sampling Surface System T cell response T memory cell T-Cell Activation Pathway T-Lymphocyte Testing Transplant Recipients Transplantation activation product allograft rejection complement pathway complement system exosome experimental study human model immunogenicity improved in vivo in vivo Model inhibitor innovation insight mouse model new therapeutic target novel post-transplant prevent process optimization receptor secondary lymphoid organ therapeutic target treatment strategy

项目摘要

Project Summary T cell mediated graft rejection remains a critical barrier to long-term graft health and survival. Post-transplant complement-induced priming of T cells and the transfer of donor major histocompatibility complexes (MHC) to recipient dendritic cells (DCs) by graft-released exosomes (commonly referred to as “cross dressing”) are both mechanistically involved in the generation of anti-donor cellular immunity. Our preliminary data newly implicate mannose binding lectin (MBL) pathway-dependent complement activation as necessary mediator for complement opsonization of exosomes and exosome-mediated donor MHC delivery to recipient DCs. Together with our prior observation that recipient MBL pathway complement activation is required for generation of robust anti-donor T cell responses and costimulatory-blockade resistant graft rejection, these data lead to our central hypothesis that post transplant MBL pathway-initiated complement activation deposits complement opsonins on exosomes, which bind to recipient DCs via complement receptors, and that this process optimizes DC “cross dressing” to permit semi-direct pathway anti-donor T cell immunity and ultimately allograft rejection. We will test this hypothesis in two specific aims. In aim 1 we will study the mechanisms required for complement activation on exosomes, characterize the effect of complement opsonins on exosome binding to recipient DCs, and test the role of DC-expressed complement receptors in our model. In aim 2 we will test for links between complement-mediated DC “cross dressing” and post-transplant anti-donor T cell immunity and transplant outcomes. The findings will be significant because a) they will provide fundamental insights into the biology of exosome function, b) provide mechanistic links between exosomes, complement, and adaptive T cell immunity, and c) potentially identify novel treatment strategies and therapeutic targets to improve transplant outcomes. Our proposal is conceptually innovative and tests a novel paradigm linking exosome function and complement activation that may have broad implications beyond the field of transplantation.

项目概要 T 细胞介导的移植物排斥仍然是移植物长期健康和存活的关键障碍。补体诱导的 T 细胞启动以及供体主要组织相容性复合物 (MHC) 的转移移植物释放的外泌体（通常称为“交叉装扮”）产生的受体树突状细胞（DC）都是我们的初步数据新表明，它在机制上参与了抗供体细胞免疫的产生。甘露糖结合凝集素（MBL）途径依赖性补体激活作为必要的介质外泌体的补体调理作用和外泌体介导的供体 MHC 递送至受体 DC。结合我们之前的观察，受体 MBL 途径补体激活是产生强大的抗供体 T 细胞反应和抗共刺激阻断移植物排斥反应，这些数据得出我们的中心假设：移植后 MBL 途径引发的补体激活沉积外泌体上的补体调理素，通过补体受体与受体 DC 结合，并且这过程优化 DC“交叉修饰”以允许半直接途径抗供体 T 细胞免疫，并最终在目标 1 中，我们将研究其机制。外泌体上补体激活所需的，表征补体调理素对外泌体的影响与受体 DC 结合，并测试 DC 表达的补体受体在我们的模型中的作用。将测试补体介导的 DC“变装”和移植后抗供体 T 细胞之间的联系这些发现将具有重要意义，因为 a) 它们将提供基础知识。深入了解外泌体功能的生物学，b) 提供外泌体、补体、和适应性 T 细胞免疫，以及 c) 潜在地确定新的治疗策略和治疗靶点我们的建议在概念上具有创新性，并测试了一种新的联系范式。外泌体功能和补体激活可能具有超出领域的广泛影响移植。