title: Down-regulation of HLA-A and HLA-Bw6, but not HLA-Bw4, allospecificities in leukemic cells: an escape mechanism from CTL and NK attack?
abstract: Human leukocyte antigen (HLA) class I antigen defects may have a negative impact on the growing application of T-cell-based immunotherapeutic strategies for treatment of leukemia. Therefore in the present study, taking advantage of a large panel of HLA class I allele-specific human monoclonal antibodies, we have compared HLA class I antigen expression on leukemic cells with that on autologous and allogeneic normal cells. Down-regulation of HLA-A and/or -B allospecificities was present in the majority of the patients studied. However, down-regulation did not affect all HLA class I alleles uniformly, but was almost exclusively restricted to HLA-A allospecificities and to HLA-B allospecificities which belong to the HLA-Bw6 group. The latter allospecificities, at variance from those that belong to the HLA-Bw4 group, do not modulate the interactions of leukemic cells with natural killer (NK) cells. Therefore, our results suggest that the selective down-regulation of HLA-A and HLA-Bw6 allospecificities associated with HLA-Bw4 preservation provides leukemic cells with an escape mechanism not only from cytotoxic T lymphocytes (CTLs), but also from NK cells. As a result T-cell-based immunotherapeutic strategies for leukemia should utilize HLA-Bw4 alloantigens as restricting elements since a selective HLA-Bw4 allele loss would provide leukemic cells with an escape mechanism from CTLs, but would increase their susceptibility to NK cell-mediated lysis.
authors.affiliation: HLA Laboratory, Academic Hospital VUB, Brussels, Belgium. christian.demanet@az.vub.ac.be
authors.forename: Christian
authors.initials: C
authors.lastname: Demanet
authors.forename: Arend
authors.initials: A
authors.lastname: Mulder
authors.forename: Veronique
authors.initials: V
authors.lastname: Deneys
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Worsham
authors.forename: Piet
authors.initials: P
authors.lastname: Maes
authors.forename: Frans H
authors.initials: FH
authors.lastname: Claas
authors.forename: Soldano
authors.initials: S
authors.lastname: Ferrone
mesh_terms: D000483:Alleles; D000911:Antibodies, Monoclonal; D000918:Antibody Specificity; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005434:Flow Cytometry; D015870:Gene Expression; D015234:HLA-A Antigens / Q000235:genetics / Q000378:metabolism*; D015235:HLA-B Antigens / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D007938:Leukemia / Q000235:genetics / Q000276:immunology*; D009154:Mutation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D015234:HLA-A Antigens; D015235:HLA-B Antigens; C042388:HLA-Bw4 antigen; C038652:HLA-Bw6 antigen