title: Class II HLA epitope matching-A strategy to minimize de novo donor-specific antibody development and improve outcomes.
abstract: De novo donor-specific antibody (dnDSA) develops in 15-25% of renal transplant recipients within 5 years of transplantation and is associated with 40% lower graft survival at 10 years. HLA epitope matching is a novel strategy that may minimize dnDSA development. HLAMatchmaker software was used to characterize epitope mismatches at 395 potential HLA-DR/DQ/DP conformational epitopes for 286 donor-recipient pairs. Epitope specificities were assigned using single antigen HLA bead analysis and correlated with known monoclonal alloantibody epitope targets. Locus-specific epitope mismatches were more numerous in patients who developed HLA-DR dnDSA alone (21.4 vs. 13.2, p < 0.02) or HLA-DQ dnDSA alone (27.5 vs. 17.3, p < 0.001). An optimal threshold for epitope mismatches (10 for HLA-DR, 17 for HLA-DQ) was defined that was associated with minimal development of Class II dnDSA. Applying these thresholds, zero and 2.7% of patients developed dnDSA against HLA-DR and HLA-DQ, respectively, after a median of 6.9 years. Epitope specificity analysis revealed that 3 HLA-DR and 3 HLA-DQ epitopes were independent multivariate predictors of Class II dnDSA. HLA-DR and DQ epitope matching outperforms traditional low-resolution antigen-based matching and has the potential to minimize the risk of de novo Class II DSA development, thereby improving long-term graft outcome.
authors.affiliation: Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Wiebe
authors.forename: D
authors.initials: D
authors.lastname: Pochinco
authors.forename: T D
authors.initials: TD
authors.lastname: Blydt-Hansen
authors.forename: J
authors.initials: J
authors.lastname: Ho
authors.forename: P E
authors.initials: PE
authors.lastname: Birk
authors.forename: M
authors.initials: M
authors.lastname: Karpinski
authors.forename: A
authors.initials: A
authors.lastname: Goldberg
authors.forename: L J
authors.initials: LJ
authors.lastname: Storsley
authors.forename: I W
authors.initials: IW
authors.lastname: Gibson
authors.forename: D N
authors.initials: DN
authors.lastname: Rush
authors.forename: P W
authors.initials: PW
authors.lastname: Nickerson
mesh_terms: D000328:Adult; D000906:Antibodies / Q000737:chemistry; D000941:Antigens / Q000737:chemistry; D015331:Cohort Studies; D000939:Epitopes / Q000737:chemistry*; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000276:immunology; D006682:HLA-DP Antigens / Q000737:chemistry; D006683:HLA-DQ Antigens / Q000737:chemistry; D006684:HLA-DR Antigens / Q000737:chemistry; D000949:Histocompatibility Antigens Class II / Q000737:chemistry*; D006650:Histocompatibility Testing; D006801:Humans; D007518:Isoantibodies / Q000276:immunology; D007668:Kidney / Q000276:immunology; D016030:Kidney Transplantation; D008875:Middle Aged; D015999:Multivariate Analysis; D011487:Protein Conformation; D012306:Risk; D014019:Tissue Donors; D016896:Treatment Outcome
chemical_list: D000906:Antibodies; D000941:Antigens; D000939:Epitopes; D006682:HLA-DP Antigens; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; D007518:Isoantibodies
keywords: Antibody-mediated rejection; donor-specific antibody; epitope; kidney transplant