Immunostimulatory CpG-oligonucleotides cause proliferation, cytokine production, and an immunogenic phenotype in chronic lymphocytic leukemia B cells.
Bacterial DNA and synthetic CpG-oligodeoxynucleotides (ODNs) derived thereof have attracted attention because they activate cells of the immune system in a sequence-dependent manner. Here we investigated the potential of CpG-ODNs to cause proliferation, cytokine production, and regulation of surface molecules in human B-chronic lymphocytic leukemia (CLL) cells. CpG-ODN induced proliferation in both B-CLL cells and normal B cells; however, only B-CLL cells increased proliferative responses when CpG-ODN was added to co-cultures of CD40-ligand transfected mouse fibroblasts (CD40LF) and B cells. Production of interleukin-6 and tumor necrosis factor alpha was detectable at borderline levels, using CpG-ODN as the only stimulus. In contrast, when CpG-ODN was added to co-cultures of B cells and CD40LF, a strong increase in cytokine production occurred in B-CLL cells as well as in normal B cells. The surface molecules CD40, CD58, CD80, CD86, CD54, and MHC class I molecules were up-regulated in B-CLL cells, whereas CD95 expression was not influenced by CpG-ODN stimulation. The same pattern of surface molecule regulation was observed in normal B cells, but up-regulation of CD40 was significantly stronger in B-CLL cells. Costimulation with CpG-ODN and CD40LF resulted in further up-regulation of CD58, CD80, CD86, and MHC class I molecules. In contrast, CD95 expression induced by CD40-ligation was inhibited by CpG-ODN. CpG-ODN activated B-CLL cells acquired a strong stimulatory capacity toward T cells in allogeneic mixed lymphocyte reaction. This effect was completely inhibited by a combination of anti-CD80 and anti-CD86 monoclonal antibody. Taken together, these findings suggest the possible use of CpG-ODN for immunotherapeutic strategies in patients with B-CLL.
Decker
T
T
IIIrd Department of Medicine and the Institute of Medical Microbiology and Hygiene, Technical University of Munich, Munich, Germany.
Schneller
F
F
Sparwasser
T
T
Tretter
T
T
Lipford
G B
GB
Wagner
H
H
Peschel
C
C
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018122:B7-1 Antigen / Q000276:immunology; D051940:B7-2 Antigen; D019013:CD40 Antigens / Q000276:immunology; D023201:CD40 Ligand; D002455:Cell Division / Q000187:drug effects; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D005347:Fibroblasts; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D005805:Genes, MHC Class I; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D006801:Humans; D016130:Immunophenotyping; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D008211:Lymphocyte Cooperation; D007959:Lymphocyte Culture Test, Mixed; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019013:CD40 Antigens; C497964:CD86 protein, human; C497965:Cd86 protein, mouse; D016207:Cytokines; D015395:Histocompatibility Antigens Class I; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand