title: Identification of 4 new HLA-DR-restricted minor histocompatibility antigens as hematopoietic targets in antitumor immunity.
abstract: Potent graft-versus-leukemia (GVL) effects can be mediated by donor-derived T cells recognizing minor histocompatibility antigens (mHags) in patients treated with donor lymphocyte infusion (DLI) for relapsed hematologic malignancies after HLA-matched allogeneic stem cell transplantation (alloSCT). Donor-derived T cells, however, may not only induce GVL, but also mediate detrimental graft-versus-host disease (GVHD). Because HLA-class II is under noninflammatory conditions predominantly expressed on hematopoietic cells, CD4+ T cells administered late after alloSCT may selectively confer GVL without GVHD. Although a broad range of different HLA-class I-restricted mHags have been identified, the first 2 autosomal HLA-class II-restricted mHags have only recently been characterized. By screening a recombinant bacteria cDNA expression library, we identified 4 new HLA-class II-restricted mHags recognized by CD4+ T cells induced in a patient with relapsed chronic myeloid leukemia who achieved long-term complete remission and experienced only mild GVHD of the skin after DLI. All CD4+ T cells were capable of recognizing the mHags presented by HLA-DR surface molecules on primary hematopoietic cells, but not on skin-derived (cytokine-treated) fibroblasts. The selective recognition of hematopoietic cells as well as the balanced population frequencies and common HLA-DR restriction elements make the novel mHags possible targets for development of immunotherapeutic strategies.
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Anita N
authors.initials: AN
authors.lastname: Stumpf
authors.forename: Edith D
authors.initials: ED
authors.lastname: van der Meijden
authors.forename: Cornelis A M
authors.initials: CA
authors.lastname: van Bergen
authors.forename: Roel
authors.initials: R
authors.lastname: Willemze
authors.forename: J H Frederik
authors.initials: JH
authors.lastname: Falkenburg
authors.forename: Marieke
authors.initials: M
authors.lastname: Griffioen
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018076:DNA, Complementary; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D051418:Focal Adhesion Kinase 2 / Q000235:genetics / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology*; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D006684:HLA-DR Antigens / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D006413:Hematopoietic System / Q000166:cytology / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics / Q000276:immunology; D015778:Minor Histocompatibility Antigens / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology; D012867:Skin / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014184:Transplantation, Homologous; D014407:Tumor Cells, Cultured
chemical_list: D015703:Antigens, CD; C093569:DEC-205 receptor; D018076:DNA, Complementary; D000939:Epitopes; D006684:HLA-DR Antigens; D015395:Histocompatibility Antigens Class I; D037181:Lectins, C-Type; C094840:MR1 protein, human; D015778:Minor Histocompatibility Antigens; D011956:Receptors, Cell Surface; C539735:MTHFD1 protein, human; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D051418:Focal Adhesion Kinase 2; C103547:PTK2B protein, human