The MHC class I MICA gene is a histocompatibility antigen in kidney transplantation

Abstract

The identity of histocompatibility loci, besides human leukocyte antigen (HLA), remains elusive. The major histocompatibility complex (MHC) class I MICA gene is a candidate histocompatibility locus. Here, we investigate its role in a French multicenter cohort of 1,356 kidney transplants. MICA mismatches were associated with decreased graft survival (hazard ratio (HR), 2.12; 95% confidence interval (CI): 1.45–3.11; P < 0.001). Both before and after transplantation anti-MICA donor-specific antibodies (DSA) were strongly associated with increased antibody-mediated rejection (ABMR) (HR, 3.79; 95% CI: 1.94–7.39; P < 0.001; HR, 9.92; 95% CI: 7.43–13.20; P < 0.001, respectively). This effect was synergetic with that of anti-HLA DSA before and after transplantation (HR, 25.68; 95% CI: 3.31–199.41; P = 0.002; HR, 82.67; 95% CI: 33.67–202.97; P < 0.001, respectively). De novo-developed anti-MICA DSA were the most harmful because they were also associated with reduced graft survival (HR, 1.29; 95% CI: 1.05–1.58; P = 0.014). Finally, the damaging effect of anti-MICA DSA on graft survival was confirmed in an independent cohort of 168 patients with ABMR (HR, 1.71; 95% CI: 1.02–2.86; P = 0.041). In conclusion, assessment of MICA matching and immunization for the identification of patients at high risk for transplant rejection and loss is warranted.

Has the Time Come for Widespread MHC Class I MICA Genotyping in Solid Organ Transplantation?

“…3 The hazard ratio for AMR among patients with both MICA and HLA preformed DSA was 25.68, P = 0.002. 3 The association between MICA antibody and allograft survival was confirmed in an independent validation cohort of 168 patients with biopsy-proven AMR. In the validation cohort, patients with anti-MICA DSA detected at the time of AMR were at higher risk for graft failure.…”

“…Donor-specific MICA antibodies identified either pretransplant or posttransplant were strongly associated with AMR (HR 3.79, P < 0.001), and the effect appeared to add to the risk of HLA DSA. 3 The hazard ratio for AMR among patients with both MICA and HLA preformed DSA was 25.68, P = 0.002. 3 The association between MICA antibody and allograft survival was confirmed in an independent validation cohort of 168 patients with biopsy-proven AMR.…”

Non-HLA Antibodies in Kidney Transplantation: Immunity and Genetic Insights

“…Among the first and most important studies to evaluate the role of anti-MICA antibodies in KT was that of Zou et al [ 59 ]. Subsequently, several studies have examined the importance of anti-MICA antibodies in KT and have shown that pre-transplant or post-transplant antibodies can be associated with the development of ABMR or TCMR and that they negatively impact kidney graft function [ 60 , 61 , 62 , 63 , 64 ]. The prevalence of anti-MICA antibodies in KT can be as high as 20% [ 65 ].…”

“…Additionally, anti-MICA antibodies could be found in the absence of sensitizing events that make the development of these antibodies through autoimmunity phenomena likely [ 66 ]. A mismatch between donor and recipient MICA alleles could lead to de novo anti-MICA donor-specific antibody formation, independent of HLA immunity [ 63 ]. These antibodies seem to exhibit synergistic action with anti-HLA antibodies, increasing the risk of rejection and graft loss [ 63 ].…”

“…A mismatch between donor and recipient MICA alleles could lead to de novo anti-MICA donor-specific antibody formation, independent of HLA immunity [ 63 ]. These antibodies seem to exhibit synergistic action with anti-HLA antibodies, increasing the risk of rejection and graft loss [ 63 ]. The possible mechanism of anti-MICA antibody graft-mediated injury could be produced through NKG2D-mediated cytotoxicity and complement-mediated cytotoxicity [ 57 ].…”