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 thereo f 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 ind uced 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-cu ltures of CD40-ligand transfected mouse fibro blasts (CD40LF) and B cells, Production of interleukin-6 and tumor necrosis factor a was detectable at b orderline 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 c ytokine production occurred in B-CLL cells as well as in normal B cells, Th e surface molecules CD40, CD58, CD80, CD86, CD54, and MHC class I molecules were up-regulated in B-CLL cells, whereas CD95 expression was not influenc ed 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 c ontrast, CD95 expression induced by CD40-ligation was inhibited by CpG-ODN. CpG-ODN activated B-CLL cells acquired a strong stimulatory capacity towar d T cells in allogeneic mixed lymphocyte reaction, This effect was complete ly inhibited by a combination of anti-CD80 and anti-CD86 monoclonal antibod y. Taken together, these findings suggest the possible use of CpG-ODN for i mmunotherapeutic strategies in patients with B-CLL. (C) 2000 by The American Society of Hematology.