A Mismatch Made in Medicine: Potential Implications of HLA DQ Epitope Mismatching Following Heart Transplantation

Abstract

Long term heart allograft survival is negatively impacted by the presence of donor specific antibodies (DSA). HLA-DQ DSA have been associated with reduced graft survival in non-heart allografts, and recent studies have indicated that HLA DR/DQ epitope mismatches may be utilized as a potential prognostic marker for de novo DSA development and subsequent graft loss in the kidney transplant population. Few studies have evaluated the presence of DQ DSA in the heart transplantation population and even fewer have examined the prognostic implications of epitope mismatches. Here, in a single center analysis, we retrospectively examine the incidence and impact of de novo DQ DSA development and the corresponding number of epitope mismatches in three adult cohorts at 1-3 years, 5 years and 10 years after heart transplantation. De-novo DQ DSA was present in 24/146 (16%) of patients transplanted at 1-3 years, 7/43 (16%) patients at 5 years and 11/46 (24%) patients at 10 years after transplant. While DQ DSA was seen more frequently in patients 10 years post-transplant, the average number of donor-recipient DQ epitope mismatches was similar (average of 23) in all groups. The presence of DQ DSA was associated with rejection, defined as biopsy-proven AMR or CAV, in 17/24 (71%) of patients at 1-3 years, 6/7 (86%) patients at 5 years and 10/11 (91%) patients at 10 years. Within each cohort, patients with greater than 20 DQ epitope mismatches were more prone to developing rejection. Immunosuppression after transplantation was protocolized and consisted of tacrolimus, mycophenolate mofetil, and an oral prednisone taper. Patients with documented medical noncompliance or subtherapeutic immunosuppression levels were not included in our analysis. While our study was underpowered to demonstrate statistical significance, our trends showed that within each cohort, in the presence of therapeutic levels of immunosuppression, patients with development of de novo DQ DSA and with a higher number of DQ epitope mismatches (greater than 20) were more prone to developing biopsy-proven AMR or CAV. Further research is required for validation. If these findings are indeed confirmed with larger studies, they could have important clinical implications that could help tailor individual immunosuppression regimens and risk-stratification strategies.