Epitope load identifies kidney transplant recipients at risk of allosensitization following minimization of immunosuppression

Abstract

HLA mismatching and minimization of immunosuppression are two major risk factors for the development of de novo donor specific antibodies, which is associated with reduced kidney graft survival. Antibodies do not recognize whole HLA antigens but rather individual epitopes, which are short sequences of amino acids in accessible positions. However, compatibility is still assessed by the simple count of mismatched HLA antigens. We hypothesized that the number of mismatched epitopes, or ("epitope load") would identify patients at the highest risk of developing donor specific antibodies following minimization of immunosuppression. We determined epitope load in 89 clinical trial participants who converted from cyclosporine to everolimus 3 months after kidney transplantation. Twentynine participants (32.6%) developed de novo donor specific antibodies. Compared to the number of HLA mismatches, epitope load was more strongly associated with the development of donor specific antibodies. Participants with an epitope load greater than 27 had a 12-fold relative risk of developing donor-specific antibodies compared to those with an epitope load below that threshold. Using that threshold, epitope load would have missed only one participant who subsequently developed donor specific antibodies, compared to 8 missed cases based on a 6-antigen mismatch. DQ7 was the most frequent antigenic target of donor specific antibodies in our population, and some DQ7 epitopes appeared to be more frequently involved than others. Assessing epitope load before minimizing immunosuppression may be a more efficient tool to identify patients at the highest risk of allosensitization.

Generation and reactivity analysis of human recombinant monoclonal antibodies directed against epitopes on HLA-DR

“…2,3 Various studies have shown an association between the number of eplet mismatches and dnDSA formation, [6][7][8] especially for HLA-DR and HLA-DQ. 9,10 Eplets resemble functional epitopes but they are not necessarily identical. A functional epitope determines the specificity of an antibody through interaction, in most cases, with the complementarity-determining region 3 of the heavy chain (CDR-H3) of the antibody.…”

Clinical importance of extended second field high-resolution HLA genotyping for kidney transplantation

“…10 2Inference tools infer the 2F-HR genotypes from the LR results based on the observed HLA allelic frequencies and haplotypes in different ethnic populations and are often used in the transplant field. [11][12][13][14] The possibility to estimate the 2F-HR HLA data brings additional confusion in the discussion about the clinical value of 2F-HR genotyping methods in the field of solid organ transplantation. 15 Although it is possible to obtain the 2F-HR genotypes correctly from the LR genotypes for some individuals, 16 it remains unknown whether such inference affects calculations of donor-recipient eplet incompatibility.…”

Transplanting the Elderly: Mandatory Age- and Minimal Histocompatibility Matching

“…As mentioned before, the Winnipeg group addressed the risk of minimization of calcineurin inhibitors and the development of dnDSA in relation to epitope mismatch load. Both studies confirmed that patients with a higher epitope load were at risk for dnDSAs after minimizing immunosuppression (56,58).…”

“…They found that epitope load was more strongly associated with dnDSAs compared to the number of serologic HLA mismatches. Of note, in this study the optimal threshold was 27 epitope mismatches (58).…”

“…However, the threshold in this study was 7 epitope mismatches for HLA-DR and 9 for HLA-DQ (57). Also, Snanoudj et al (58) investigated the epitope mismatch load by using HLA Matchmaker in 89 renal recipients. They found that epitope load was more strongly associated with dnDSAs compared to the number of serologic HLA mismatches.…”