title: Identification of phosphatidylinositol 4-kinase type II beta as HLA class II-restricted target in graft versus leukemia reactivity.
abstract: Patients with hematological malignancies can be successfully treated with HLA-matched T cell-depleted allogeneic stem cell transplantation (alloSCT) and subsequent donor lymphocyte infusions (DLIs). The efficacy of DLI is mediated by donor T cells recognizing minor histocompatibility antigens (mHags) on malignant recipient cells. Because HLA class II molecules are predominantly expressed on hematopoietic cells, mHag-specific CD4(+) T cells may selectively mediate graft versus leukemia (GvL) reactivity without graft versus host disease (GvHD). In this study, we used a recombinant bacteria cDNA library for the identification of the first autosomal HLA class II (HLA-DQB1*0603)-restricted mHag LB-PI4K2B-1S encoded by the broadly expressed phosphatidylinositol 4-kinase type II beta gene. A polyclonal CD4(+) T cell response against LB-PI4K2B-1S was demonstrated in a patient with relapsed chronic myeloid leukemia (CML) who responded to DLI after HLA-matched alloSCT. LB-PI4K2B-1S-specific CD4(+) T cells recognized and lysed the CD34(+) CML cells of the patient and other leukemic cells as well as high HLA-DQ-expressing normal hematopoietic cells. HLA-DQ expression on normal cells of nonhematopoietic origin was moderately up-regulated by IFN-gamma and not sufficient for T cell recognition. We hypothesize that LB-PI4K2B-1S-specific CD4(+) T cells contributed to the antitumor response by both directly eliminating malignant cells as effector cells and stimulating CD8(+) T cell immunity as helper cells.
authors.affiliation: Departments of Hematology and Immunohematology and Blood Transfusion, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands. m.griffioen@lumc.nl
authors.forename: Marieke
authors.initials: M
authors.lastname: Griffioen
authors.forename: Edith D
authors.initials: ED
authors.lastname: van der Meijden
authors.forename: Elisabeth H
authors.initials: EH
authors.lastname: Slager
authors.forename: M Willy
authors.initials: MW
authors.lastname: Honders
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Rutten
authors.forename: Simone A P
authors.initials: SA
authors.lastname: van Luxemburg-Heijs
authors.forename: Peter A
authors.initials: PA
authors.lastname: von dem Borne
authors.forename: Johannes J
authors.initials: JJ
authors.lastname: van Rood
authors.forename: Roel
authors.initials: R
authors.lastname: Willemze
authors.forename: J H Frederik
authors.initials: JH
authors.lastname: Falkenburg
mesh_terms: D019870:1-Phosphatidylinositol 4-Kinase / Q000737:chemistry / Q000276:immunology*; D000595:Amino Acid Sequence; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002469:Cell Separation; D002999:Clone Cells; D018076:DNA, Complementary / Q000235:genetics; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D006087:Graft vs Host Reaction / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000276:immunology; D059866:HLA-DQ beta-Chains; D006413:Hematopoietic System / Q000166:cytology / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D007938:Leukemia / Q000201:enzymology* / Q000276:immunology*; D008969:Molecular Sequence Data; D009928:Organ Specificity; D010455:Peptides / Q000737:chemistry / Q000276:immunology
chemical_list: D018076:DNA, Complementary; D000939:Epitopes; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D000949:Histocompatibility Antigens Class II; D010455:Peptides; D019870:1-Phosphatidylinositol 4-Kinase