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

供体先天免疫反应在心脏移植后调节同种免疫中的作用

基本信息

批准号：
10405512
负责人：
Daniel Kreisel
金额：
$ 63.66万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10405512
关键词：
Ablation Admixture Adverse effects Allograft Tolerance Allografting Apoptosis Applications Grants Automobile Driving Blood Circulation Cardiac Cardiac Myocytes Cell Death Cell model Cells Clinical Collaborations Cues Cytokine Signaling Development Endothelial Cells Event Foundations Goals Graft Enhancements Graft Rejection Graft Survival Heart Heart Transplantation Heart failure Heterogeneity Human Immune Immune Targeting Immune response Immunologics Infection Inflammation Inflammatory Inflammatory Response Innate Immune Response Interferon Type I Intervention Leukocyte Trafficking Leukocytes Life Link Mediating Medicine Molecular Mouse Strains Mus Nature Neutrophil Infiltration Organ Organ Transplantation Outcome Pathogenesis Pathway interactions Patients Pattern Phase Plasma Cells Play Population Process Production Publications Regimen Reperfusion Injury Reperfusion Therapy Reporting Research Research Personnel Role Shapes Signal Transduction Solid Surface TLR4 gene Techniques Testing Time Tissues Transplant Recipients Transplantation Work allograft rejection base experimental study graft dysfunction high risk improved improved outcome innate immune pathways insight intravital microscopy isoimmunity macrophage monocyte novel novel therapeutics prevent recruit response side effect single-cell RNA sequencing success treatment choice treatment strategy

项目摘要

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.

项目摘要/摘要心脏移植的成功受到缺血再灌注损伤介导的原发性移植功能障碍的限制以及同种异体移植排斥，这两个可能在免疫学上连接的过程。当前减少移植的策略排斥和改善的生存率主要基于受体免疫细胞群体的消融。这些方法仅是适度有效的，并具有威胁生命的感染的高风险。替代方案潜在更安全的方法是靶向供体移植物中的免疫途径和细胞群体炎症反应和导致的同种异体反应性。精确控制初始免疫反应的能力遵循心脏移植代表了一种有希望的方法来增加同种异体移植的耐受性并提高临床结果。我们最近的工作确定了铁铁作用，一种炎症细胞死亡的一种非凋亡形式心脏移植物再灌注后介导早期炎症反应。我们发现了移植物内皮细胞和组织居民CCR2+巨噬细胞在促进将炎性免疫细胞募集到移植的心脏。在此提案中，我们将使用最先进的艺术技术，包括插入式显微镜，单细胞RNA测序和新型小鼠菌株研究的研究1）定义细胞死亡的机制（AIM1），2）评估细胞特异性炎症的作用细胞因子信号传导（AIM 2）和3）检查心脏巨噬细胞异质性的作用（AIM 3）在驱动先天心脏移植后的炎症和同种免疫反应。我们的研究将为小说奠定基础治疗将改善心脏移植后的预后。