The Role of Donor Innate Immune Responses in Regulating Alloimmunity after Heart Transplantation

项目摘要/摘要 心脏移植的成功受限于缺血再灌注损伤所致的移植物功能障碍 和同种异体移植排斥反应，这两个过程可能在免疫学上有联系。当前减少贪污的策略 排斥反应和提高存活率主要建立在去除受体免疫细胞群的基础上。这些 这些方法只能起到一定的效果，而且感染危及生命的风险很高。一种替代方案， 潜在更安全的方法是针对供者移植物内启动的免疫通路和细胞群 炎症反应和由此产生的同种异体反应。精确控制初始免疫反应的能力 心脏移植后是增加同种异体移植耐受性和改善的一种有希望的方法 临床结果。我们最近的工作发现，铁性下垂是一种非凋亡性的炎性细胞死亡形式 介导心脏移植物再灌流后的早期炎症反应。我们发现，贪污 内皮细胞和组织驻留的CCR2巨噬细胞在促进 炎性免疫细胞向移植心脏的募集。在这份提案中，我们将使用最新的- ART技术，包括活体显微镜、单细胞RNA测序和新的小鼠品系 研究将1)确定细胞死亡的机制(Aim1)，2)评估细胞特异性炎症的作用 细胞因子信号转导(目标2)和3)研究心脏巨噬细胞异质性(目标3)在推动先天发育中的作用 心脏移植后的炎症和同种异体免疫反应。我们的研究将为小说的创作奠定基础 将改善心脏移植后结果的治疗。

PROJECT SUMMARY/ABSTRACT The success of heart transplantation is limited by ischemia reperfusion injury-mediated primary graft dysfunction and allograft rejection, two processes that may be immunologically linked. Current strategies to reduce graft rejection and improve survival are mostly based on ablation of recipient immune cell populations. These approaches are only modestly effective and carry high risks of life-threatening infections. An alternative and potentially safer approach is to target immune pathways and cell populations within the donor graft that initiate inflammatory responses and resultant alloreactivity. The ability to precisely control the initial immune response following heart transplantation represents a promising approach to increase allograft tolerance and improve clinical outcomes. Our recent work has identified that ferroptosis, a non-apoptotic form of inflammatory cell death mediates the early inflammatory response after reperfusion of heart grafts. We have discovered that graft endothelial cells and tissue-resident CCR2+ macrophages play important and complementary roles in promoting the recruitment of inflammatory immune cells to the transplanted heart. In this proposal, we will use state-of-the- art techniques, including intravital microscopy, single cell RNA sequencing and novel mouse strains to perform studies that will 1) define mechanisms of cell death (Aim1), 2) evaluate the role of cell-specific inflammatory cytokine signaling (Aim 2) and 3) examine the role of cardiac macrophage heterogeneity (Aim 3) in driving innate inflammatory and alloimmune responses after heart transplantation. Our studies will lay the foundation for novel therapy that will improve outcomes after cardiac transplantation.