Innate Allorecognition and Kidney Transplant Outcomes

Background: Donor-recipient mismatches in histocompatibility antigens recognized by adaptive immune cells adversely affect allograft outcomes. Whether mismatches sensed by innate immune cells have a similar effect is unclear. Methods: SIRPA alleles encode signal regulatory protein-α that activate monocytes by binding to CD47.We investigated the effect of SIRPA mismatch on kidney allograft pathology and survival in mice and humans. We asked if eliminating the SIRPA mismatch or CD47 ameliorates chronic kidney allograft pathology in the mouse; analyzed SIRPA polymorphism in 5008 publicly available human genome sequences; and interrogated associations between SIRPA donor-recipient mismatch and allograft pathology and 7-yr graft survival in a cohort of 455 kidney transplant patients and validated these observations in an independent cohort of 258 patients. Finally, we compared circulating monocyte phenotype between SIRPA matched and mismatched patients. Results: Eliminating the Sirpa mismatch or recipient CD47 prevented chronic allograft pathology in major histocompatibility antigen mismatched mouse kidney allografts (NOD to B6 vs. NOD.B6.SIRPa to B6 vs. NOD to B6 CD47-/- transplants). Human genomic analysis identified 10 common haplotypes that segregated into two categories, A and B, encoding SIRPa variants with different CD47 binding interfaces. Transplantation between a B donor and an A recipient was associated with increased acute rejection (AR, OR, 2.3; 95% CI, 1.3-3.9; p=0.004) and graft fibrosis (OR, 4.3; 95% CI, 2.1-9.2; p=0.0001) in the first post-transplant year. Moreover, these patients had a 3-fold increase in the incidence of persistent AR in the 1st year and a further 3-fold increase in late clinical AR beyond the 1st post-transplant year compared to the matched patients. Finally, B->A mismatched patients had worse 7-year death-censored (HR, 3.2; 95% CI, 1.5-6.9; p=0.002) and overall (HR, 2.0, p=0.003) graft survival compared to matched patients. The effect of SIRPA mismatch on graft outcomes was independent of ancestry, relatedness, HLA mismatch, DSA, and DGF, and was validated in the independent cohort. Assessment of peripheral blood monocytes in mismatched patients revealed an activated phenotype irrespective of AR diagnosis. Conclusion: SIRPA donor-recipient mismatch that causes innate immune activation is an important determinant of kidney transplantation outcomes and could be a potential risk stratification tool. Funding: Other NIH Support - NIAID