Interaction between HLA-B leader peptide variants and cytomegalovirus serostatus is associated with early T cell-mediated rejection in kidney transplantation

Mismatches between mature recipient and donor HLA proteins can trigger alloreactivity upon transplantation. Recent studies suggest that also the leader peptide of HLA class I alleles may affect the transplantation outcome. In this retrospective study, we examined the association between the HLA-B leader -21 methionine (M)/threonine (T) dimorphism and T cell-mediated rejection (TCMR) early after kidney transplantation. In a hypothesis-generating cohort of 351 transplants, -21MM recipients experienced significantly increased odds of early TCMR within the first 90 days post-transplantation compared to -21TT recipients (odds ratio (OR) 4.57, 95% confidence interval (CI) 1.87-10.95, p<0.001), irrespective of the donor's HLA-B leader peptide. This association was most prominent among CMV-seropositive recipients (OR 10.91, 95% CI 3.24-39.24, p<0.001). In an independent cohort (n=936), -21MM CMV-seropositive recipients seemed to be at increased odds of early TCMR. In parallel, among CMV-seropositive recipients, -21MT recipients had a significantly increased likelihood of developing early TCMR (OR 2.74, 95% 1.08-7.88, p=0.04). Combined, CMV-seropositivity in the presence of a -21M leader peptide associated with early TCMR with an OR of 2.95 (95% CI 1.49-5.86, p=0.002). In both cohorts, the effect of the -21M leader peptide was most prominent among recipients mismatched for an HLA-A/-C leader peptide. Conclusively, this study suggests that recipients with an HLA-B -21M leader peptide have increased odds of early TCMR, which is further influenced by the recipient's CMV serostatus. While the underlying mechanism remains speculative, these findings indicate that the HLA-B leader peptide of the recipient may affect immune regulation and early TCMR after kidney transplantation.