HLA and MICA: Targets of Antibody-Mediated Rejection in Heart Transplantation

Abstract

Background The goal of this study was to determine whether antidonor antibodies directed against human leukocyte antigen (HLA) or endothelial cells (ECs) expressed antigens, including major histocompatibility complex class I chain-related antigens A (MICA) are associated with the diagnosis of antibody-mediated rejection (AMR) in heart transplant recipients. Methods We studied posttransplant antidonor HLA antibodies in 168 heart allograft recipients transplanted from October 2001 to December 2005. Among them, there were 37 AMR + patients and 131 age- and sex- matched AMR − controls. Sera were collected at the time of protocol biopsies and tested for the presence of HLA antibodies. Seventy-two of the 168 patients were genotyped for donor and recipient MICA alleles and were tested for the presence of anti-MICA antibodies. Thirty-one patients who never developed antibodies to HLA or MICA were further tested for anti-EC antibodies. Results and Conclusions Of 37 AMR + patients, 22 (60%) developed donor-specific antibodies (DSA) to HLA compared with 6 of 131(4%) AMR − patients (P<0.0001). Of the remaining 15 AMR + patients, 5 had anti-HLA antibodies that were not donor specific and 10 did not show any HLA antibodies. In the subgroup of 72 patients, all 19 AMR + patients had clearly demonstrable antibodies reactive with donor HLA, MICA or with nondonor-derived ECs, with 30% of them showed antibodies directed to non-HLA antigens. The incidence of transplant coronary artery disease was significantly higher in patients who had DSA to HLA and MICA compared with patients without DSA.

MICA Variant Promotes Allosensitization after Kidney Transplantation

“…41 An initial report showing that MICA molecules, expressed at the endothelial cell surface, are recognized by specific antibodies in recipients 14 has been sustained by clinical studies showing the detrimental effect of anti-MICA sensitization in kidney, heart, and lung transplantation. 15,17,42,43 Nevertheless, the molecular basis for MICA alloimmunization remains to be established. 44 Here, we show that MICA A5.1 molecules are primary targets for post-transplant antibodies in kidney allograft recipients because of higher MICA expression associated with this mutation.…”

Acute and chronic antibody-mediated rejection in pediatric kidney transplantation

“…Independently, non-HLA antibodies have been demonstrated to play a major role in the pathogenesis of antibody-mediated rejection [32][33][34][35]. In particular, non-HLA antibodies against endothelial antigens such as the major histocompatibility complex class I-related chain A (MICA) cause antibody-mediated rejection in transplantation patients [36,37]. Moreover, anti-endothelial cell antibodies against other known endothelial surface antigens such as the angiotensin II type 1-receptor, vimentin and collagen V or against unknown antigens have been implicated in antibodymediated rejection after kidney transplantation [32,34].…”

Transplant coronary heart disease: challenges and solutions

“…In a retrospective study by Nath et al, 38 67% of patients with angiographic evidence of CAV had DSAs against HLA or MICA, whereas 33% of patients without CAV had these DSAs. In a similar manner, Zhang et al 39 concluded that patients with DSAs against HLA or MICA had a 77% survival free of CAV at 2 years, defined by angiographic stenosis of .50%, compared with 96% in those without these DSAs. However, neither study correlated DSA with complement activation, endothelial function, or intimal thickening.…”