The relevance and impact of MICA allele mismatching and MICA antibodies on renal transplantation outcome

Even when kidney allografts are well matched for HLA antigens and anti-HLA antibodies are undetected, graft rejection still occurs. There is evidence of hyperacute rejection in the absence of HLA antibodies, implicating other alloantigens. Studies have shown that some patients with graft rejection or loss have antibodies specific for the highly polymorphic MHC class I-related chain A (MICA) antigens. This thesis investigated whether mismatching MICA alleles associates with MICA antibody production and graft rejection, survival or dysfunction. Using commercial assays, MICA and HLA antibody screening of 442 recipients was performed and specificities were confirmed in a sub-group of 227 recipients using single antigen (SAg) multiplex technology. MICA antibody specificity was assigned using three independent SAg assays. In addition, MICA alleles of 227 recipients and donors were determined by development and application of DNA sequence based typing. Acute rejection (AR) was assessed by renal pathologists and classified as acute cellular rejection (ACR) or acute antibody-mediated rejection (aAMR). Graft function was assessed by estimated glomerular filtration rate (eGFR) and serum creatinine measurements. Among the cohort of 442 recipients, 33 (7.5%) produced MICA antibodies, which correlated with ACR (P=0.03). Analysis of the MICA typed cohort revealed 17 patients (7.5%) had MICA antibodies and 13 (6%) developed MICA donor-specific antibodies (DSA). Multivariate analysis revealed MICA mismatching as a significant factor associated with the presence of MICA antibodies (P=0.009) and 14 mismatched MICA residues significantly correlated with MICA antibody production. MICA and HLA antibodies significantly associated with AR and MICA-DSA and HLA-DSA correlated with decreased graft function by univariate and multivariate analysis. To conclude, mismatching of specific MICA epitopes in renal transplantation is a mechanism leading to production of MICA antibodies and MICA-DSA that associate with AR and graft dysfunction.