Retransplant candidates have donor-specific antibodies that react with structurally defined HLA-DR,DQ,DP epitopes

Abstract

This report describes a detailed analysis how donor-specific HLA class II epitope mismatching affects antibody reactivity patterns in 75 solid organ transplant recipients with an in situ allograft and who were considered for retransplantation. Sera were tested for antibodies in a sensitive antigenbinding assay (Luminex) with single class II alleles. Their reactivity was analyzed with HLAMatchmaker, a structural matching algorithm that considers so-called eplets to define epitopes recognized by antibodies. Only 24% of the patients showed donor-specific anti-DRB1 antibodies and there was a significant correlation with a low number of mismatched DRB1 eplets. This low detection rate of anti-DRB1 antibodies may also be due to allograft absorption. In contrast, antibodies to DRB3/4/5 mismatches were more common. Especially, 83% of the DRB4 (DR53) mismatches resulted in detectable antibodies against an eplet uniquely found on DR53 antigens. Donor-specific DQB mismatches led to detectable anti-DQB antibodies with a frequency of 87%. Their specificity correlated with eplets uniquely found on DQ1-4. The incidence of antibodies induced by 2-digit DQA mismatches was 64% and several eplets appeared to play a dominant role. These findings suggest that both α and β chains of HLA-DQ heterodimers have immunogenic epitopes that can elicit specific antibodies. About one-third of the sera had anti-DP antibodies; they reacted primarily with two DPB eplets and an allelic pair of DPA eplets.These data demonstrate that HLA class II reactive sera display distinct specificity patterns associated with structurally defined epitopes on different HLA-D alleles.

HLA-DR and -DQ Eplet Mismatches and Transplant Glomerulopathy: A Nested Case–Control Study

“…67LR, 71RRA, 4Q, 71DRA and 32IYN) and were deemed immunogenic previously (i.e. 4Q and 71DRA) (37,41). In contrast, some previously reported immunogenic HLA-DQ eplet mismatches (37,41) appeared more frequently among the controls (see Tables S3 and S4).…”

“…There has been a growing recognition that HLA antibodies are directed toward structurally defined HLA epitopes (60) rather than HLA antigens (21,25,26). Duquesnoy et al (37), for example, showed that patients with DRB1/3/4/5 antibodies were exposed to twice as many mismatched eplets as those who did not show antibodies (21.4 AE 8.0 vs. 10.6 AE 7.8, p < 0.0001). More recently, Wiebe et al (41) showed a similar association between the number of locus-specific epitope mismatches and the development of de novo anti-HLA-DR and anti-HLA-DQ antibodies.…”

“…Our inability to observe a doseresponse relationship between TG and HLA-DQ eplet load categories defined by tertiles may be related to the relatively small sample size. Alternatively, the immunogenicity (the ability to induce an antibody response) and antigenicity (the reactivity with specific antibodies) of particular eplet contributing to the eplet load may play a role (37,41).…”

“…Finally, we report the most frequent eplet mismatches among cases versus controls (i.e. observed in >20% of TG cases and their frequency among controls !10% lower than cases) and evaluate those against previously identified immunogenic eplets (37,41).…”

“…These residues have been termed ''eplets'' (32)(33)(34)(35). HLAMatchmaker (http://www.hlamatchmaker.net) is a computer algorithm that identifies structural HLA eplet mismatches between donors and recipients that may give rise to anti-HLA antibodies (31,33,(36)(37)(38)(39)(40).…”