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长期移植物健康和存活的关键障碍。移植后 补体诱导的T细胞致敏和供体主要组织相容性复合物（MHC）转移到 通过移植物释放的外泌体（通常称为"异装"）的受体树突状细胞（DC） 其在机制上参与抗供体细胞免疫的产生。我们的初步数据显示 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， 外来体的补体调理作用和外来体介导的供体MHC向受体DC的递送。 结合我们先前的观察，受体MBL途径补体激活是需要的， 产生稳健的抗供体T细胞应答和共刺激阻断抗性移植物排斥，这些 数据导致我们的中心假设，即移植后MBL途径启动的补体激活沉积 外泌体上的补体调理素，其通过补体受体与受体DC结合，并且这 该过程优化了DC "交叉修饰"，以允许半直接途径抗供体T细胞免疫， 同种异体移植排斥反应。我们将在两个具体目标中检验这一假设。在目标1中，我们将研究 补体调理素是补体激活外泌体所必需的，表征补体调理素对外泌体的作用 结合受体DC，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， 将测试补体介导的DC "交叉修饰"和移植后抗供体T细胞之间的联系， 免疫和移植结果。这些发现将是重要的，因为a）它们将提供基本的 对外来体功能的生物学的了解，B）提供外来体，补体， 和适应性T细胞免疫，以及c）潜在地鉴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， 外泌体功能和补体激活可能具有超出免疫学领域的广泛影响。 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.