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

项目概要/摘要 缺血再灌注损伤介导的原发性移植物功能障碍限制了心脏移植的成功 和同种异体移植排斥，这两个过程可能在免疫学上有联系。减少贪污的现行策略 排斥和提高存活率主要基于受体免疫细胞群的消除。这些 这些方法的效果有限，而且存在感染危及生命的高风险。一种替代的和 潜在的更安全的方法是靶向供体移植物内的免疫途径和细胞群， 炎症反应和由此产生的同种异体反应性。精确控制初始免疫反应的能力 在心脏移植后，代表了一种有希望的方法，以增加同种异体移植物的耐受性， 临床结果。我们最近的工作已经确定，铁凋亡，一种非凋亡形式的炎性细胞死亡， 介导心脏移植物再灌注后的早期炎症反应。我们发现， 内皮细胞和组织驻留的CCR 2+巨噬细胞在促进细胞增殖中发挥重要和互补的作用。 炎症免疫细胞向移植心脏的募集。在本提案中，我们将使用- 艺术技术，包括活体显微镜，单细胞RNA测序和新的小鼠品系，以执行 这些研究将1）确定细胞死亡的机制（Aim 1），2）评估细胞特异性炎症反应的作用， 细胞因子信号传导（Aim 2）和3）检查心脏巨噬细胞异质性（Aim 3）在驱动先天性 炎症和同种免疫反应。我们的研究将为小说奠定基础 这将改善心脏移植后的结果。

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.