Immunostimulatory CpG Oligodeoxynucleotides Enhance the Immune Response to Vaccine Strategies Involving Granulocyte-Macrophage Colony-Stimulating Factor

Abstract

Immunostimulatory oligodeoxynucleotides containing the CpG motif (CpG ODN) can activate various immune cell subsets and induce production of a number of cytokines. Prior studies have demonstrated that both CpG ODN and granulocyte-macrophage colony-stimulating factor (GM-CSF) can serve as potent vaccine adjuvants. We used the 38C13 murine lymphoma system to evaluate the immune response to a combination of these two adjuvants. Immunization using antigen, CpG ODN, and soluble GM-CSF enhanced production of antigen-specific antibody and shifted production towards the IgG2a isotype, suggesting an enhanced TH1 response. This effect was most pronounced after repeat immunizations with CpG ODN and antigen/GM-CSF fusion protein. A single immunization with CpG ODN and antigen/GM-CSF fusion protein 3 days before tumor inoculation prevented tumor growth. CpG ODN enhanced the production of interleukin-12 by bone marrow-derived dendritic cells and increased expression of major histocompatibility complex class I and class II molecules, particularly when cells were pulsed with antigen/GM-CSF fusion protein. We conclude that the use of CpG ODN in combination with strategies involving GM-CSF enhances the immune response to antigen and shifts the response towards a TH1 response and that this approach deserves further evaluation in tumor immunization approaches and other conditions in which an antigen-specific TH1 response is desirable.

Particulate adjuvants can induce macrophage survival, DNA synthesis, and a synergistic proliferative response to GM-CSF and CSF-1

“…In support of this additional possibility, it should be noted that GM-CSF, a cytokine with adjuvant activity, also induces the survival and proliferation of cells of the monocyte/macrophage lineage, including BMDM [30]. GM-CSF is produced at sites of immune and inflammatory reactions and the synergistic proliferative response reported above between the active adjuvants and GM-CSF may have some in vivo significance, particularly because GM-CSF and other adjuvants appear to demonstrate synergy in potentiating immune reactions in vivo [29]. As mentioned, the synergistic proliferative effect with low doses of CSF-1 could also be significant because monocytes/macrophages in vivo are likely to be exposed continuously to such low doses in several tissues [10][11][12].…”

“…Monocyte-macrophage lineage cells may be exposed to GM-CSF at sites of inflammation or immune reactions [27,28]; also GM-CSF and other adjuvants can show synergy in the potentiation of immune responses [29]. We had previously reported that oxLDL can synergize with GM-CSF for BMDM DNA synthesis even at optimal GM-CSF concentrations [13].…”

Co‐delivery of GM‐CSF gene enhances the immune responses of hepatitis C viral core protein‐expressing DNA vaccine: Role of dendritic cells

“…The difference in CTL activity, however, was not as striking as core-speci®c antibody, which might be due the secreted nature of the fusion protein by expression vector in the study. Reports from other studies are still controversial, some showing that GM-CSF can activate both Th1 and Th2 immune responses whereas others report that GM-CSF stimulates only either Th1 or Th2 response [Okada et al, 1997;Liu et al, 1998;Sin et al, 1998;Stamp¯i et al, 1998]. The balance of activation of DC1 or DC2 by GM-CSF plasmid DNA injection might be one of the factors to result in these Th1 and Th2 responses [Pulendran et al, 1999;Rissoan et al, 1999].…”

Adjuvant effects of CpG oligodeoxynucleotides on responses against T‐independent type 2 antigens

“…antibody-forming cells by adult and neonatal splenocytes. 21 In vivo, CpG-ODN are shown here to essentially enhance adult IgG2a responses to TNP-Ficoll, similar to their in¯uence on IgG2a responses to protein vaccines 22,23 and model protein antigens. 24±27 This`T helper type 1 driving' immunomodulatory property of CpG-ODN has been largely associated with their capacity to enhance IL-12 production by APC, 28 which suggests that TNP-Ficoll responses may be in¯uenced by APC activation.…”