Innate Allorecognition in Clinical Organ Transplantation

临床器官移植中的天然同种异体识别 移植后第一年同种异体器官的缓慢损耗(长期移植物丢失) 这是临床移植中的一个重要问题。我们在这份拨款申请中假设 天然同种异体识别-移植细胞上同种异体决定簇对受体单核细胞的激活- 是肾移植受者长期移植物丢失的重要驱动因素。先天同种异体识别 刺激单核细胞分化为抗原提呈、细胞毒性和先天记忆细胞 传播适应性同种免疫反应或直接造成移植物损伤。一把钥匙 负责先天同种异体识别和记忆的同种异体是多态的 跨膜分子信号调节蛋白α(SIRPA)。基于引人入胜的鼠标 和人类数据，我们建议在目标1中测试SIRPA不匹配的临床假设 供者和受者是慢性同种异体免疫损伤的重要独立危险因素 长期的移植物损失。两大批供者/受者肾移植对 将对细粒临床和常规活检数据进行基因分型和研究。在目标2中， 我们将测试机械假设，即SIRPA错配的不利影响是 通过受体单核细胞的激活和分化来调节。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。我们认为这项提议意义重大，因为SIRPA基因分型 策略可以很容易地转化为临床实践，获得的机械性见解可以导致 可下药的目标。这项提议是创新的，因为它探索了一个新的概念，先天 同种异体识别，这超越了传统的以T、B和抗体为中心的排斥方法 这是一个问题，也是一个尚未在人类身上探索的问题。

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.