Elucidating the role of trained immunity in kidney transplant patients

摘要-项目1 历史上，器官移植免疫学家一直专注于适应性免疫系统，就像器官排斥反应一样。 主要由T细胞介导。然而，越来越多的证据表明，先天免疫细胞具有独特的作用。 在复杂的移植物反应性免疫反应中。这位P01‘S的研究人员建议调节先天免疫 以训练有素的免疫为目标的反应，先天免疫功能反应性的长期增加 细胞，它由表观遗传修饰维持，可以被认为是事实上的先天免疫记忆。 项目1的成员最近在同种异体心脏移植的小鼠模型中证明了移植物 排斥反应可以通过治疗调节训练有素的免疫力来预防。压制训练有素的免疫力 一种耐受的环境，其特征是调节性巨噬细胞和调节性T细胞在 异体移植。移植物微环境的这种变化导致了移植物的长期存活，而不需要 免疫抑制疗法。这些结果得到了肾移植患者的初步数据的证实， 表明训练有素的免疫力与移植物10年的存活率有关。基于这些基础上的基础和临床 初步数据，项目1的S总体假设是经过训练的免疫促进了肾脏的移植排斥反应 移植病人。 在目标1中，我们将研究哪些循环因子(例如，危险相关的分子模式和促炎 细胞因子)是移植过程中缺血再灌注损伤的结果，以及这些影响是如何 通过诱导训练有素的免疫使移植物存活。持久训练的免疫需要骨骼的表观遗传变化 骨髓祖细胞。在目标2中，我们将研究骨髓的变化如何影响 循环单核细胞的产生和行为，并与临床结果相关，包括移植物存活。 为了实现这些目标，我们组建了一个由项目负责人Dr领导的多学科研究团队。 穆德将协调项目1并监督一个经验丰富的同事团队：Duivenvoorden博士是一名 Mhlanga博士和Mhlanga博士将负责肾移植患者的研究 Netea将与Core C密切合作，负责所有的RNA和ATAC测序工作。 项目1将对训练有素的免疫和移植肾存活之间的关系产生重要的见解。 移植病人。这些见解将为推进患者护理开辟新的诊断和治疗途径。

SUMMARY – PROJECT 1 Historically, organ transplant immunologists have focused on the adaptive immune system, as organ rejection is mediated primarily by T cells. However, accumulating evidence indicates a distinct role for innate immune cells in the complex graft-reactive immune response. This P01’s investigators propose to modulate innate immune responses by targeting trained immunity, a long-term increase in the functional responsiveness of innate immune cells, which is maintained by epigenetic modifications and can be considered de facto innate immune memory. The members of Project 1 recently demonstrated in a mouse model of heart allograft transplantation that graft rejection can be prevented by therapeutically regulating trained immunity. Suppressing trained immunity yielded a tolerogenic milieu characterized by an accumulation of regulatory macrophages and regulatory T cells in the allograft. This change in the allograft microenvironment resulted in long-term graft survival without requiring immunosuppressive therapy. These results are corroborated by preliminary data in kidney transplant patients, showing that trained immunity is associated with 10-year graft survival. Based on these preclinical and clinical preliminary data, Project 1’s overall hypothesis is that trained immunity promotes graft rejection in kidney transplant patients. In Aim 1, we will study which circulating factors (e.g., danger-associated molecular patterns and proinflammatory cytokines) are produced as a result of ischemia-reperfusion injury during transplantation and how these impact graft survival by inducing trained immunity. Durable trained immunity requires epigenetic changes in bone marrow myeloid progenitors. In Aim 2, we will investigate how changes in the bone marrow influence the production and behavior of circulating monocytes and relate this to clinical outcomes, including graft survival. To accomplish these Aims, we have assembled a multidisciplinary team of investigators led by Project Lead Dr. Mulder, who will coordinate Project 1 and supervise a team of experienced co-Is: Dr. Duivenvoorden is a transplant nephrologist and will be responsible for the studies on kidney transplant patients, Drs. Mhlanga and Netea will be responsible for all RNA- and ATAC-sequencing in close collaboration with Core C. Project 1 will yield critical insights into the relation between trained immunity and graft survival in kidney transplant patients. These insights will open new diagnostic and therapeutic avenues for advancing patient care.