title: Identification of 4 novel HLA-B*40:01 restricted minor histocompatibility antigens and their potential as targets for graft-versus-leukemia reactivity.
abstract: BACKGROUND
  Patients with hematologic malignancies can be successfully treated with donor lymphocyte infusion after HLA-matched allogeneic hematopoietic stem cell transplantation. The effect of donor lymphocyte infusion is mediated by donor T cells recognizing minor histocompatibility antigens. T cells recognizing hematopoietic restricted minor histocompatibility antigens may induce selective graft-versus-leukemia reactivity, whereas broadly-expressed antigens may be targeted in graft-versus-host disease.
  
  
  METHODS
  We analyzed in detail CD8(+) T-cell immunity in a patient with relapsed chronic myelogenous leukemia who responded to donor lymphocyte infusion with minimal graft-versus-host disease of the skin. CD8(+) T-cell clones specific for 4 HLA-B*40:01 restricted minor histocompatibility antigens were isolated which were identified by screening a plasmid cDNA library and whole genome association scanning. Detailed T-cell reactivity and monitoring experiments were performed to estimate the clinical and therapeutic relevance of the novel antigens.
  
  
  RESULTS
  Three antigens were demonstrated to be expressed on primary leukemic cells of various origins as well as subtypes of non-malignant hematopoietic cells, whereas one antigen was selectively recognized on malignant hematopoietic cells with antigen presenting cell phenotype. Skin derived fibroblasts were only recognized after pre-treatment with IFN-γ by two T-cell clones.
  
  
  CONCLUSIONS
  Our data show evidence for different roles of the HLA-B*40:01 restricted minor histocompatibility antigens in the onset and execution of the anti-tumor response. All antigens may have contributed to a graft-versus-leukemia effect, and one minor histocompatibility antigen (LB-SWAP70-1Q) has specific therapeutic value based on its in vivo immunodominance and strong presentation on leukemic cells of various origins, but absence of expression on cytokine-treated fibroblasts.
authors.affiliation: Department of Hematology, C2-R, 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: M Willy
authors.initials: MW
authors.lastname: Honders
authors.forename: Edith D
authors.initials: ED
authors.lastname: van der Meijden
authors.forename: Simone A P
authors.initials: SA
authors.lastname: van Luxemburg-Heijs
authors.forename: Ellie G A
authors.initials: EG
authors.lastname: Lurvink
authors.forename: Michel G D
authors.initials: MG
authors.lastname: Kester
authors.forename: Cornelis A M
authors.initials: CA
authors.lastname: van Bergen
authors.forename: J H Frederik
authors.initials: JH
authors.lastname: Falkenburg
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015723:Gene Library; D006086:Graft vs Host Disease / Q000235:genetics* / Q000276:immunology*; D059947:HLA-B40 Antigen / Q000235:genetics* / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000276:immunology / Q000628:therapy; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens / Q000235:genetics* / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014184:Transplantation, Homologous
chemical_list: D059947:HLA-B40 Antigen; D015778:Minor Histocompatibility Antigens