Scholar Presentation: Innate Alloimmunity: SIRPA mismatches between the donor and recipient are associated with kidney allograft outcome

Aim: Recent data suggest that innate immune cells can also recognize and respond to genetic differences between donors
and recipients, "innate allorecognition". This study investigates whether mismatches in the polymorphic gene encoding
signal regulatory protein α (SIRPA) that regulates the function of monocytes, dendritic cells, and macrophages, impact
kidney allograft survival.

Methods: This retrospective observational cohort study included 455 renal transplant pairs from the University of
Pittsburgh Medical Center (UPMC) and 258 transplant pairs from Northwestern Memorial Hospital, Northwestern
University (NU). SIRPA typing was performed using three sets of primers to identify the presence of A and B alleles.

Results: Compared to the UPMC cohort, the NU patients were less likely to be Caucasian, received better HLA-matched
allografts all from living donors, received Alemtuzumab as induction therapy and 24% were maintained on
corticosteroids. Based on SIRPA genotypes, patients were classified as M matched (UPMC=38%, NU=51%), A→B
mismatched if more A alleles were present in the recipient (UPMC=33%, NU=30%), and B→A mismatched if more B
alleles were present in the donor (UPMC=29%, NU=19%). We investigated the impact of SIRPA mismatches on longterm death-censored allograft survival by Kaplan Meier method. In the discovery UPMC cohort, patients with B→A
mismatched allografts had the worse 7-year death-censored allograft survival (75% vs. 92%, p=0.001 compared to the
matched group) (Figure 1A). Similarly, death-censored allograft survival was significantly lower at 4 years in the B→A
mismatched group than the matched group in the validation cohort (85% vs. 95%, p=0.04) (Figure 1B). Additionally,
SIRPA B→A mismatch was associated with increased rates of acute rejection and allograft fibrosis in the first posttransplant year. Finally, the multivariable cox analysis for the combined cohorts (n=713) confirmed the independent
impact of the B→A mismatch on the allograft survival with HR of 2.5 (95%CI, 1.4-4.6; p=0.002).

Conclusion: This study found that a specific SIRPA mismatch, B→A mismatch, is associated with an increased risk of
acute rejection, fibrosis, and impaired allograft survival after kidney transplant. This is likely due to the activation of
recipient monocytes that occur when SIRPA 'B' kidneys are transplanted into SIRPA 'A' recipients.