Analysis of T and B Cell Epitopes to Predict the Risk of de novo Donor-Specific Antibody (DSA) Production After Kidney Transplantation: A Two-Center Retrospective Cohort Study

Abstract

Risk prediction of de novo donor specific antibody (DSA) would be very important for long term graft outcome after organ transplantation. The purpose of this study was to elucidate the association of eplet mismatches and predicted indirectly recognizable HLA epitopes (PIRCHE) scores with de novo DSA production. Our retrospective cohort study enrolled 691 living donor kidney transplantations. HLA-A, B, DRB and DQB eplet mismatches and PIRCHE scores (4 digit of HLA-A, B, DR, and DQ) were determined by HLA matchmaker (ver 2.1) and PIRCHE-II Matching Service, respectively. Weak correlation between eplet mismatches and PIRCHE scores was identified, although both measurements were associated with classical HLA mismatches. Class II (DRB+DQB) eplet mismatches were significantly correlated with the incidence of de novo class II (DR/DQ) DSA production [8/235 (3.4%) in eplet mismatch ≤ 13 vs. 92/456 (20.2%) in eplet mismatch ≥ 14, p < 0.001]. PIRCHE scores were also significantly correlated with de novo class II DSA production [26/318 (8.2%) in PIRCHE ≤ 175 vs. 74/373 (19.8%) in PIRCHE ≥ 176, p < 0.001]. Patients with low levels of both class II eplet mismatches and PIRCHE scores developed de novo class II DSA only in 4/179 (2.2%). Analysis of T cell and B cell epitopes can provide a beneficial information on the design of individualized immunosuppression regimens for prevention of de novo DSA production after kidney transplantation.

Peptides Derived From Mismatched Paternal Human Leukocyte Antigen Predicted to Be Presented by HLA-DRB1, -DRB3/4/5, -DQ, and -DP Induce Child-Specific Antibodies in Pregnant Women

“…With regard to ii), our data confirm previous reports about the correlation between the number of HLA-derived peptides being presented on HLA-DRB1 and CSA in the pregnancy setting or DSA in the transplantation setting (4,8,26). Moreover, we showed correlations between numbers of HLA-DRB3/4/5-, -DQ-, and -DPpresented HLA-derived peptides and HLA antibody responses (Figure 5 and Table 1).…”

“…As shown previously, predicting DSA after organ transplantation with numerically combined Eplet mismatch numbers and PS is superior compared with the predictions based on the independent scores (26). Alongside further improvements of Eplet matching (28,29), the herein presented modification of the PIRCHE algorithm thus may improve the combined predictions.…”

Computational Eurotransplant kidney allocation simulations demonstrate the feasibility and benefit of T-cell epitope matching

“…Epitope matching can significantly improve the outcome of HLA-mismatched kidney transplantation [19,20,22,23,32]. Therefore, allocation based on matching for epitope compatibility rather than matching for serological antigen may be beneficial.…”

“…HLA-DQA1/-DQB1 heterodimers to CD4+ T cells. [22] After further clinical validation, implementation of corresponding typing methods in the pre-transplant diagnostic routine and upon availability of haplotype frequency datasets including HLA-DQA1 and HLA-DP, the presented workflow might be adapted to simulate enhanced PIRCHE-II scores' impact on allocation.…”

“…This model can predict indirect CD4+ T-cell recognition of allo-HLA derived peptides [16,17], a concept which is highly involved in graft failure after solid organ transplantation (review by Siu et al [21]). Recent studies have shown that predicted donor-HLA derived epitopes presented on HLA class-II molecules, designated as PIRCHE-II, are related to HLA antibody formation [19,22]. Moreover, other retrospective organ transplantation studies using the PIRCHE algorithm have shown that T-cell epitope matching indeed leads to an improved transplant outcome [20,23].…”