Elucidating the role of trained immunity in kidney transplant patients

阐明训练有素的免疫力在肾移植患者中的作用

• 批准号: 10642596
• 负责人: Willem Mulder
• 金额: $ 31.04万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642596
• 关键词: ATAC-seq; Academic Medical Centers; Acute; Adaptive Immune System; Affect; Allografting; Antigens; Automobile Driving; B-Lymphocytes; Behavior; Biological Markers; Bone Marrow; Bone Marrow Aspiration; Cells; Clinical; Collaborations; Complex; Data; Epigenetic Process; Foundations; Gene Expression Profiling; Graft Rejection; Graft Survival; Heart Transplantation; Hematopoietic stem cells; Human; Immune; Immune response; Immunity; Immunologic Memory; Immunologic Tests; Immunologist; Immunotherapeutic agent; In Vitro; Incubated; Infiltration; Inflammation; Inflammatory; Innate Immune Response; Kidney Transplantation; Lead; Leukocytes; Macrophage; Mediating; Modification; Molecular; Myelogenous; Natural Immunity; Natural Killer Cells; Organ Transplantation; Outcome; Pathway interactions; Patient Care; Patients; Pattern; Play; Production; Regulatory T-Lymphocyte; Reperfusion Injury; Research Personnel; Role; Sampling; Serum; T-Lymphocyte; Testing; Therapeutic; Therapeutic immunosuppression; Training; Transplant Recipients; Transplantation; Transplantation Immunology; Work; adaptive immune response; adaptive immunity; antimicrobial; biobank; cytokine; design; diagnostic tool; epigenetic profiling; experience; fluorodeoxyglucose positron emission tomography; follow-up; heart allograft; insight; longitudinal, prospective study; member; monocyte; mouse model; multidisciplinary; multiple omics; nano; nanobiologic; non-invasive imaging; nonhuman primate; novel; novel diagnostics; novel therapeutics; organ transplant rejection; post-transplant; pre-clinical; prevent; progenitor; programs; response; transcriptome sequencing

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.

摘要 – 项目 1 从历史上看，器官移植免疫学家一直关注适应性免疫系统，因为器官排斥是 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，P01 的研究人员提出调节先天免疫。 通过针对训练有素的免疫来做出反应，先天免疫功能反应的长期增加 细胞，这是通过表观遗传修饰维持的，可以被认为是事实上的先天免疫记忆。 项目1的成员最近在小鼠心脏同种异体移植模型中证明了移植物 可以通过治疗性调节训练有素的免疫力来预防排斥反应。 一种致耐受环境，其特征是调节性巨噬细胞和调节性 T 细胞在 同种异体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。 免疫抑制治疗的结果得到了肾移植患者的初步数据的证实， 根据这些临床前和临床结果表明，经过训练的免疫力与 10 年移植物存活率相关。 初步数据，项目1的总体假设是训练有素的免疫力促进肾脏移植排斥 移植患者。 在目标 1 中，我们将研究哪些循环因素（例如，危险相关分子模式和促炎性因子） 移植过程中缺血再灌注损伤产生的细胞因子）及其影响 通过诱导训练有素的免疫力来维持移植物的存活。持久的训练有素的免疫力需要骨骼的表观遗传变化。 在目标 2 中，我们将研究骨髓的变化如何影响骨髓祖细胞。 循环单核细胞的产生和行为，并将其与临床结果（包括移植物存活）联系起来。 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。 Mulder，他将协调项目 1 并监督一支由经验丰富的同事组成的团队：Duivenvoorden 博士是一名 Mhlanga 博士和移植肾病专家将负责肾移植患者的研究。 Netea 将与 Core C 密切合作，负责所有 RNA 和 ATAC 测序。 项目 1 将对训练后的免疫力与肾脏移植物存活之间的关系产生重要的见解 这些见解将为推进患者护理开辟新的诊断和治疗途径。