Leukocyte trafficking in thoracic grafts

项目摘要/摘要 心血管疾病和心力衰竭在退伍军人中非常普遍。心脏 移植仍然是终末期心力衰竭患者的首选治疗方法。 然而，心脏移植后的预后受到原发移植物功能障碍的不利影响， 缺血再灌注损伤的后果。原发移植物功能障碍导致直接组织 并可增强引发移植物排斥反应的适应性免疫反应。目前，有 心脏移植后原发移植物功能障碍无有效治疗方法及处理 这些患者中大部分是支持性的。我们的实验室已经开发出体内成像平台， 使我们能够实时观察白细胞在小鼠心脏移植物中的渗透情况。穿过 这些方法，我们发现了细胞和分子的线索，以规范贩运 中性粒细胞和单核细胞是已知的介导组织损伤的先天免疫细胞，进入 移植的心脏。我们的发现提出了一个耐人寻味的前景，即靶向免疫途径和细胞 供者移植物内的群体可以控制心脏后的初始免疫反应 移植。在之前的资助期间，我们发现了一种非上睑下垂，即一种 细胞死亡的凋亡形式介导了心脏移植物再灌注后的早期炎症反应。 我们已经报道，移植物内皮细胞和组织驻留的CCR2巨噬细胞发挥关键和 在推动中性粒细胞向移植心脏募集中的互补作用。现在我们有了 产生的初步数据表明，额外的捐赠者免疫细胞群和信号 这些途径调节白细胞向心脏移植物的募集。在这个提案中，我们将使用最先进的 技术包括活体双光子显微镜，新的正电子发射断层扫描探头， 单细胞RNA测序和新的小鼠品系进行研究，以确定供体的作用 非经典单核细胞(Aim 1)和TREM-1/3信号转导(Aim 2)在促炎中的作用 缺血型心脏移植物再灌注后的反应。我们的研究将为小说的创作奠定基础 将改善心脏移植接受者和患者预后的治疗 其他条件所致的心肌缺血再灌注损伤。

Project Summary / Abstract Cardiovascular disease and heart failure are highly prevalent among the veteran population. Cardiac transplantation remains a preferred therapy for patients who suffer from end-stage heart failure. However, outcomes after heart transplantation are adversely impacted by primary graft dysfunction, a consequence of ischemia reperfusion injury. Primary graft dysfunction causes immediate tissue damage and can also augment adaptive immune responses that trigger graft rejection. Currently, there are no effective therapies for primary graft dysfunction after heart transplantation and the management of these patients is mostly supportive. Our laboratory has developed intravital imaging platforms that has allowed us to visualize the infiltration of leukocytes into murine heart grafts in real time. Through these approaches we have uncovered cellular and molecular cues that regulate the trafficking of neutrophils and monocytes, innate immune cells that are known to mediate tissue damage, into transplanted hearts. Our findings raise the intriguing prospect that targeting immune pathways and cell populations within the donor graft can control the initial immune response following heart transplantation. During the previous funding period we have discovered that ferroptosis, a non- apoptotic form of cell death mediates the early inflammatory response after reperfusion of heart grafts. We have reported that graft endothelial cells and tissue-resident CCR2+ macrophages play critical and complementary roles in driving the recruitment of neutrophils to the transplanted heart. Now we have generated preliminary data showing that additional donor immune cell populations and signaling pathways regulate leukocyte recruitment to cardiac grafts. In this proposal, we will use state-of-the-art techniques including intravital two-photon microscopy, new positron emission tomography probes, single cell RNA sequencing and novel murine strains to perform studies that will define the role of donor non-classical monocytes (Aim 1) and TREM-1/3 signaling (Aim 2) in promoting inflammatory responses after reperfusion of ischemic heart grafts. Our studies will lay the foundation for novel therapies that will improve outcomes for heart transplant recipients and patients who suffer from myocardial ischemia reperfusion injury due to other conditions.