title: Up-regulated expression in nonhematopoietic tissues of the BCL2A1-derived minor histocompatibility antigens in response to inflammatory cytokines: relevance for allogeneic immunotherapy of leukemia.
abstract: T cells directed against hematopoietic-restricted minor histocompatibility antigens (mHags) may mediate graft-versus-leukemia (GVL) reactivity without graft-versus-host disease (GVHD). Recently, the HLA-A24-restricted mHag ACC-1 and the HLA-B44-restricted mHag ACC-2 encoded by separate polymorphisms within the BCL2A1 gene were characterized. Hematopoietic-restricted expression was suggested for these mHags. We demonstrate BCL2-related protein A1 (BCL2A1) mRNA expression in mesenchymal stromal cells (MSCs) that was up-regulated by the inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and/or interferon gamma (IFN-gamma). Analysis of cytotoxicity and IFN-gamma production illustrated that ACC-2-specific T cells did not recognize untreated MSCs or IFN-gamma-treated MSCs but showed specific recognition and killing of MSCs treated with TNF-alpha plus IFN-gamma. We hypothesize that under steady-state circumstances BCL2A1-specific T cells may exhibit relative specificity for hematopoietic tissue, but reactivity against nonhematopoietic cells may occur when inflammatory infiltrates are present. Thus, the role of BCL2A1-specific T cells in differential induction of GVL reactivity and GVHD may depend on the presence of inflammatory responses that may occur during GVHD.
authors.affiliation: Department of Hematology, Leiden University Medical Center, C2-R, PO Box 9600, 2300 RC Leiden, The Netherlands. f.m.kloosterboer@lumc.nl
authors.forename: Freke M
authors.initials: FM
authors.lastname: Kloosterboer
authors.forename: Simone A P
authors.initials: SA
authors.lastname: van Luxemburg-Heijs
authors.forename: Ronald A
authors.initials: RA
authors.lastname: van Soest
authors.forename: H M Esther
authors.initials: HM
authors.lastname: van Egmond
authors.forename: Roel
authors.initials: R
authors.lastname: Willemze
authors.forename: J H Frederik
authors.initials: JH
authors.lastname: Falkenburg
mesh_terms: D016207:Cytokines / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology*; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D007938:Leukemia / Q000276:immunology* / Q000628:therapy; D008297:Male; D015778:Minor Histocompatibility Antigens / Q000235:genetics / Q000276:immunology*; D011110:Polymorphism, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D015854:Up-Regulation
chemical_list: C096816:BCL2-related protein A1; D016207:Cytokines; D015778:Minor Histocompatibility Antigens; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma