The Timing of GM-CSF Expression Plasmid Administration Influences the Th1/Th2 Response Induced by an HIV-1-Specific DNA Vaccine

Abstract

The mechanism of immune activation induced by a plasmid-encoding GM-CSF (pGM-CSF), administered in combination with a DNA vaccine encoding the envelope of HIV, was studied. Injecting pGM-CSF i.m. into mice 3 days before DNA vaccination primarily induced a Th2 response. Simultaneous administration of the DNA vaccine plus pGM-CSF activated both a Th1 and a Th2 response. When the plasmid was injected 3 days after DNA vaccination, enhancement of Th1 immunity predominated. These results suggest that the timing of cytokine expression determines the phenotype of the resultant Th response. After 3 days of pGM-CSF injection, the increased percentages of CD11c+, CD8+ cells were observed in the regional lymph nodes. In addition, many infiltrated cells, including S-100 protein-positive cells, were found in the pGM-CSF-injected tissue. The importance of these S-100+ cells or both CD8+ and CD11c+ cells, especially that of dendritic cells (DCs), was also studied. DCs derived from bone marrow and cultured in RPMI 1640 medium containing IL-4 and GM-CSF were incubated with DNA vaccine and then transferred into naive mice. Mice receiving DCs showed strong HIV-1-specific Th2 immune responses. Our results suggest that DCs play important roles in the activation or modification of the Th2-type immune response induced by DNA vaccination.

Th2-dominated antitumor immunity induced by DNA immunization with the genes coding for a basal core peptide PDTRP and GM-CSF

“…GM-CSF administration before target gene inoculation polarized the response to a Th2 type, whereas a Th1 type response could be induced when GM-CSF was administered after target gene inoculation. 19 Thus, GM-CSF may be a neutral cytokine that serves as an amplifier for either a Th1 or a Th2 response depending on the context and the timing of DNA vaccine. GM-CSF could amplify Th1 or Th2 immune responses depending on different strains of mice used in the various studies.…”

“…For example, Pulendran et al found that polarized Th1 type immune responses were induced by GM-CSF via either cell vaccine or DNA immunization. [16][17][18] Okada et al 13 demonstrated that the Th2 immune responses were induced by intranasal vaccine, 13 and Kusakabe et al 19 found that Th2 immune responses were induced by injection of a GM-CSF plasmid before the injection of plasmid containing the target antigens.…”

Immunogenicity and safety profiles of genetic vaccines against human Her-2/neu in cynomolgus monkeys

“…32,33 Although immunization with engineered tumor cells secreting low levels of GM-CSF generated measurable increases in antitumor effect, highdose expression of GM-CSF instead impaired the immune responses by inducing the recruitment of myeloid-derived suppressor cells. 34 GM-CSF may also promote tumor cell transmigration through the endothelial barrier 35 and high levels of GM-CSF secreted by cancer cells were shown to promote osteolytic bone metastasis.…”

Immunity against breast cancer by TERT DNA vaccine primed with chemokine CCL21

“…30 The amino acid sequence of hTERT was analyzed for the 8-10 amino-acid peptide binding sequences for H-2K d using two computer programs, BIMAS and SYFPEITHI. 31 The COOH-terminal end of hTERT (cTERT code for amino acids 795-1132) contains peptide sequences found to have higher scores by the programs.…”

“…IgG2a are associated with predominantly T-helper 1 (TH1) responses. 22,31 The CCL21/cTERT vaccine induced significantly higher IgG2a (Po0.0005) titers compared to the cTERT alone vaccine both in the prophylactic and the therapeutic vaccine models (Table 1). Both the cTERT alone vaccine and CCL21 alone failed to induce strong IgG2a responses.…”