title: Mismatched HLA-DRB3 Can Induce a Potent Immune Response After HLA 10/10 Matched Stem Cell Transplantation.
abstract: Donors for allogeneic stem cell transplantation 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 alloimmune responses. Mismatches in HLA-DRB3, 4, and 5 are usually not taken into account in donor selection.
  
  
  
  Conversion of chimerism in the presence of GVHD after CD4 donor lymphocyte infusion was observed in a patient, HLA 10/10 matched, but mismatched for HLA-DRB3 and HLA-DPB1 compared with the donor. Alloreactive CD4 T cells were isolated from peripheral blood after CD4 donor lymphocyte infusion and recognition of donor-derived target cells transduced with the mismatched patient variant HLA-DRB3 and HLA-DPB1 molecule was tested.
  
  
  
  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.
  
  
  
  In contrast to the assumption that mismatches in HLA-DRB3, 4, and 5 are not of immunogenic significance after HLA 10/10 matched allogeneic stem cell transplantation, 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.
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: van Balen
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Simone A P
authors.initials: SAP
authors.lastname: van Luxemburg-Heijs
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Marian
authors.initials: M
authors.lastname: van de Meent
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Cornelis A M
authors.initials: CAM
authors.lastname: van Bergen
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Constantijn J M
authors.initials: CJM
authors.lastname: Halkes
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Inge
authors.initials: I
authors.lastname: Jedema
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: J H Frederik
authors.initials: JHF
authors.lastname: Falkenburg
mesh_terms: D000483:Alleles; D001787:Blood Group Incompatibility; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D046528:Chimerism; D006086:Graft vs Host Disease / Q000276:immunology; D006680:HLA Antigens / Q000276:immunology*; D006682:HLA-DP Antigens / Q000276:immunology; D006683:HLA-DQ Antigens / Q000276:immunology; D059826:HLA-DRB3 Chains / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology* / Q000628:therapy*; D012074:Remission Induction; D033581:Stem Cell Transplantation; D013601:T-Lymphocytes / Q000276:immunology*; D014019:Tissue Donors; D014184:Transplantation, Homologous; D016896:Treatment Outcome
chemical_list: D006680:HLA Antigens; D006682:HLA-DP Antigens; D006683:HLA-DQ Antigens; D059826:HLA-DRB3 Chains