Epitope Spreading and Epitope Sharing Are Involved in Acute IgG1 Antibody-Mediated Rejection of a Kidney Transplant with Disparity Only at HLA-DP

B. Mierzejewska, P. Schroder, C. Baum, A. Blair, R. Duquesnoy, M. Marrari, M. Rees, S. Stepkowski

University of Toledo, Toledo, OH
University of Pittsburgh, Pittsburgh, PA

Meeting: 2013 American Transplant Congress

Abstract number: B958

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 1^st 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) 2^nd transplant failed within 1 year due to chronic rejection. The 3^rd transplant was mismatched only for DPA1*02:01 and DPB1*01:01/*04:02. Although prior to the 3^rd 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 1^st and 3^rd 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 1^st transplant and DPB1*01:01 of the 3^rd transplant (Fig. 1). The DSA after the 1^st 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 3^rd transplant (panels A, B, and C). Furthermore, two immunizing epitopes (35YA and 84DEAV) on DPB1*11:01 of the 1^st transplant (panel D) conferred reactivity to DPB1*01:01 of the 3^rd 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 November 22, 2024.

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