Complement-Mediated Exosome Function in Transplantation

项目摘要 T细胞介导的移植物排斥反应仍然是移植物长期健康和存活的关键障碍。移植后 补体诱导的T细胞启动和供体主要组织相容性复合体(MHC)向T细胞的转移 受体树突状细胞(DC)由移植物释放的外体(通常被称为“交叉敷料”)既是 机械地参与了抗供体细胞免疫的产生。我们的初步数据新牵连到 甘露糖结合凝集素(MBL)途径依赖的补体激活作为必要的调节因子 外切体的补体调理及外切体介导的供体MHC向受体DC的递送。 再加上我们先前的观察，受体MBL途径补体激活是必需的 产生强大的抗供体T细胞反应和共刺激-阻断抵抗移植物排斥，这些 这些数据导致了我们的中心假设，移植后MBL途径启动的补体激活沉积 外体上的补体调色素，通过补体受体与受体树突状细胞结合，这 Process优化DC“变装”，允许半直接途径抗捐献者T细胞免疫，并最终 同种异体排斥反应。我们将在两个具体目标上检验这一假设。在目标1中，我们将研究这些机制 外切体上补体激活所必需的，表征补体调理素对外切体的影响 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。在《目标2》中，我们 将检测补体介导的DC“变装”与移植后抗供者T细胞之间的联系 免疫力和移植结果。这些发现将具有重大意义，因为a)它们将提供基本的 对外切体功能的生物学的洞察，b)提供外切体之间的机械联系，补充， 和适应性T细胞免疫，以及c)可能确定新的治疗策略和治疗靶点 改善移植结果。我们的建议在概念上是创新的，并测试了一种新的范式链接 外切体功能和补体激活，可能具有超越领域的广泛影响 移植。

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.