Innate Allorecognition in Clinical Organ Transplantation

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.