Innate Allorecognition in Clinical Organ Transplantation

临床器官移植中的先天同种异体识别

• 批准号: 10560678
• 负责人: Fadi G. Lakkis
• 金额: $ 73.45万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-20 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560678
• 关键词: Acceleration; Acute; Adult; Adverse effects; Allogenic; Allografting; Antibodies; Antigen Presentation; Applications Grants; Arterial Disorder; B-Lymphocytes; Biopsy; Biopsy Specimen; Cells; Cessation of life; Chronic; Clinic; Clinical; Coupled; Data; Dendritic Cells; Failure; Fibrosis; Gene Expression Profile; Genes; Genetic Transcription; Genotype; Graft Survival; HLA Antigens; Human; Immune system; Immunosuppression; Inflammation; Injury; Kidney Transplantation; Living Donors; Longevity; Macrophage; Mediating; Membrane; Memory; Molecular; Mus; Organ; Organ Survival; Organ Transplantation; Outcome; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Protocols documentation; Risk; Risk Factors; Role; SHPS-1 protein; Signaling Molecule; T-Lymphocyte; Testing; Time; Translating; Transplant Recipients; Transplantation; adaptive immune response; clinical practice; cohort; cytotoxic; donor-specific antibody; druggable target; graft failure; graft function; human data; human leukocyte antigen testing; improved; innovation; insight; interstitial; kidney allograft; memory acquisition; monocyte; novel; novel therapeutics; peripheral blood; post-transplant; premature; response; sobriety; statistics

Innate Allorecognition in Clinical Organ Transplantation Slow attrition of organ allografts after the first post-transplant year (long-term graft loss) remains a significant problem in clinical transplantation. We hypothesize in this grant application that innate allorecognition – the activation of recipient monocytes by allodeterminants on graft cells – is an important driver of long-term graft loss in kidney transplant recipients. Innate allorecognition stimulates monocyte differentiation into antigen-presenting, cytotoxic, and innate memory cells that propagate the adaptive alloimmune response or cause graft damage directly. A key allodeterminant responsible for innate allorecognition and memory is the polymorphic transmembrane molecule Signal Regulatory Protein Alpha (SIRPa). Based on compelling mouse and human data, we propose to test in Aim 1 the clinical hypothesis that SIRPa mismatch between the donor and recipient is a significant, independent risk factor for chronic alloimmune injury and long-term graft loss. Two large cohorts of donor/recipient kidney transplant pairs on whom granular clinical and protocol biopsy data are available will be genotyped and studied. In Aim 2, we will test the mechanistic hypothesis that the adverse effects of SIRPa mismatching are mediated via recipient monocyte activation and differentiation. Phenotypic, transcriptional, and functional analysis will be performed on peripheral blood monocytes, coupled with spatial profiling of biopsy samples. We believe that the proposal is significant because the SIRPa genotyping strategy can be readily translated to clinical practice, and mechanistic insights gained can lead to druggable targets. The proposal is innovative because it explores a novel concept, innate allorecognition, that goes beyond the traditional T, B, and Ab-centric approaches to the rejection problem and one that has not been explored in humans yet.

临床器官移植中的先天同种异体识别 移植后第一年后同种异体移植器官的缓慢消耗（长期移植物损失）仍然存在 我们在这项拨款申请中追求的一个重大问题是 先天同种异体识别 – 通过移植细胞上的同种异体决定簇激活受体单核细胞 – 是肾移植受者长期移植物损失的重要驱动因素。 刺激单核细胞分化为抗原呈递细胞、细胞毒性细胞和先天记忆细胞 传播适应性同种免疫反应或直接导致移植物损伤。 负责先天同种异体识别和记忆的同种异体决定因素是多态性 跨膜分子信号调节蛋白 Alpha (SIRPa) 基于引人注目的小鼠。 和人类数据，我们建议在目标 1 中测试 SIRPa 之间不匹配的临床假设 供体和受体是慢性同种免疫损伤的一个重要的、独立的危险因素 两大组供体/受体肾移植对的长期移植损失。 在目标 2 中，将对可获得的详细临床和方案活检数据进行基因分型和研究。 我们将检验 SIRPa 不匹配的不利影响的机制假设 通过受体单核细胞激活和分化介导。 将对外周血单核细胞进行功能分析，并结合空间分析 我们认为该提案意义重大，因为 SIRPa 基因分型。 策略可以很容易地转化为临床实践，并且获得的机制见解可以导致 该提案具有创新性，因为它探索了一个新颖的概念：固有的。 同种异体识别，超越了传统的以 T、B 和 Ab 为中心的排斥方法 人类尚未探索过的问题。