Background: Donor-specific alloantibodies (DSA) directed to HLA-DP alone may cause acute antibody-mediated rejection (AMR), especially in re-transplanted patients. Since the origins of such DSA are not clear, we have examined the sensitization history of a patient who received 3 consecutive kidney transplants.
Methods/Results: Single antigen bead (SAB) analysis showed immunization by the 1st transplant with multiple class I/II HLA mismatches; this transplant lasted 9 years and was lost to chronic nephropathy. The HLA-matched (except for DRB3*02:02 and DPB1*04:02) 2nd transplant failed within 1 year due to chronic rejection. The 3rd transplant was mismatched only for DPA1*02:01 and DPB1*01:01/*04:02. Although prior to the 3rd transplant the patient had 100% PRA and DPA1*02:01-reactive DSA in SAB (3518 MFI), the flow crossmatch (FXM) was negative. Within 10 days, the patient had elevated creatinine (3 mg/dL) and C4d+ AMR (Banff 2a). This correlated with DSA of IgG1 (but no other subclasses) directed to DPA1*02:01 in SAB (18483 MFI) and SAB-C1q (25940 MFI) as well as to DPB1*01:01 in SAB (5359 MFI). HLAMatchmaker analysis revealed that the 1st and 3rd transplants shared 4, recipient mismatched, epitopes (111R, 51RA, 83A, 127P) on DPA1*02:01 as well as 2 epitopes (35YA, 84DEAV) on DPB1*11:01 of the 1st transplant and DPB1*01:01 of the 3rd transplant (Fig. 1). The DSA after the 1st transplant towards one immunizing epitope (111R) on DPA1*02:01 was joined by reactivity to three additional epitopes (51RA, 83A and 127P) during AMR after the 3rd transplant (panels A, B, and C). Furthermore, two immunizing epitopes (35YA and 84DEAV) on DPB1*11:01 of the 1st transplant (panel D) conferred reactivity to DPB1*01:01 of the 3rd transplant (panel E).
Conclusions: 1) DP alleles alone induce acute AMR in previously immunized patients; 2) FXM fails to detect DSA to DP alleles detectable by SAB assay; and 3) both epitope spreading and epitope sharing enhance IgG1-mediated DSA leading to robust acute AMR.
To cite this abstract in AMA style:Mierzejewska B, Schroder P, Baum C, Blair A, Duquesnoy R, Marrari M, Rees M, Stepkowski S. Epitope Spreading and Epitope Sharing Are Involved in Acute IgG1 Antibody-Mediated Rejection of a Kidney Transplant with Disparity Only at HLA-DP [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/epitope-spreading-and-epitope-sharing-are-involved-in-acute-igg1-antibody-mediated-rejection-of-a-kidney-transplant-with-disparity-only-at-hla-dp/. Accessed October 20, 2020.
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