Mismatched HLA-DRB3 can induce a potent immune response after HLA 10/10 matched stem cell transplantation.

Background: Donors for allogeneic stem cell transplantation (alloSCT) are preferentially matched with patients for HLA-A, B, C and DRB1. Mismatches between donor and patient in these alleles are associated with an increased risk of graft-versus-host disease (GVHD). In contrast, HLA-DRB3, 4 and 5, HLA-DQ and HLA-DP are usually assumed to be low expression loci with limited relevance, although mismatches in HLA-DQ and HLA-DP can result in allo-immune responses. Mismatches in HLA-DRB3, 4 and 5 are usually not taken into account in donor selection. Methods: Conversion of chimerism in the presence of GVHD after CD4 donor lymphocyte infusion (DLI) was observed in a patient, HLA 10/10 matched, but mismatched for HLA-DRB3 and HLA-DPB1 compared to the donor. Alloreactive CD4 T cells were isolated from peripheral blood after CD4 DLI and recognition of donor derived target cells transduced with the mismatched patient variant HLA-DRB3 and HLA-DPB1 molecule was tested. Results: A dominant polyclonal CD4 T cell response against patient's mismatched HLA-DRB3 molecule was found in addition to an immune response against patient's mismatched HLA-DPB1 molecule. CD4 T cells specific for these HLA class II molecules recognized both hematopoietic target cells as well as GVHD target cells. Conclusion: In contrast to the assumption that mismatches in HLA-DRB3, 4 and 5 are not of immunogenic significance after HLA 10/10 matched alloSCT, we show that in this matched setting not only mismatches in HLA-DPB1, but also mismatches in HLA-DRB3 may induce a polyclonal allo-immune response associated with conversion of chimerism and severe GVHD. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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