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.