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.

FIGURE 1

Posttransplant human leukocyte antigen (HLA) and major histocompatibility complex class I chain-related antigens A (MICA) donor-specific antibodies (DSA) increases the probability of transplant coronary artery disease (TCAD). TCAD-free survival at 2 years posttransplant was significantly lower in the 26 patients with anti-donor HLA and MICA antibodies compared with 46 patients without DSA (P<0.02).

FIGURE 2

Human leukocyte antigen (HLA) antibodies were tested in all 168 institutional review board-consented recipients. Major histocompatibility complex class I chain-related antigens A (MICA) antibody studies were limited to 72 of the 168 recipients for whom DNA was available on both the donor and recipient for MICA genotyping. Anti-endothelial antibodies were performed on 31 of the 72 recipients who tested negative for antibodies to HLA or MICA study population.