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.

先天性同种异体识别在临床器官移植中的应用 移植后第一年（长期移植物丢失）的器官移植物缓慢磨损仍然存在 临床移植中的一个重要问题。我们在这份拨款申请中假设， 先天性同种异体识别-受体单核细胞被移植细胞上的同种异体决定簇激活， 是肾移植受者长期移植物丢失的重要驱动因素。先天性同种识别 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引起移植物损伤。一个关键 负责先天同种识别和记忆的同种决定簇是多态的 跨膜分子信号调节蛋白α（SIRPa）。基于引人注目的鼠标 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重要独立危险因素， 长期移植物丢失。两个大型队列的供体/受体肾移植对， 颗粒临床和方案活检数据可用，将进行基因分型和研究。在目标2中， 我们将检验SIRPa不匹配的不利影响是 通过受体单核细胞活化和分化介导。表型、转录和 将对外周血单核细胞进行功能分析，并结合空间分析 活组织检查样本。我们认为该建议是重要的，因为SIRPa基因分型 策略可以很容易地转化为临床实践，获得的机械见解可以导致 可下药的目标该提案具有创新性，因为它探索了一个新颖的概念， 同种异体识别，这超越了传统的T，B，和Ab中心的方法拒绝 这是一个尚未在人类身上探索过的问题。