Modulation of amplitude and direction ofin vivo immune responses by co-administration of cytokine gene expression cassettes with DNA immunogens

Abstract

Immunization with nucleic acids has been shown to induce both antigen-specific cellular and humoral immune responses in vivo. We hypothesize that immunization with DNA could be enhanced by directing specific immune responses induced by the vaccine based on the differential correlates of protection known for a particular pathogen. Recently we and others reported that specific immune responses generated by DNA vaccine could be modulated by co-delivery of gene expression cassettes encoding for IL-12, granulocyte-macrophage colony-stimulating factor and the co-stimulatory molecule CD86. To further engineer the immune response in vivo, we investigated the induction and regulation of immune responses following the co-delivery of pro-inflammatory cytokine (IL-1 alpha, TNF-alpha, and TNF-beta), Th1 cytokine (IL-2, IL-12, IL-15, and IL-18), and Th2 cytokine (IL-4, IL-5 and IL-10) genes. We observed enhancement of antigen-specific humoral response with the co-delivery of Th2 cytokine genes IL-4, IL-5, and IL-10 as well as those of IL-2 and IL-18. A dramatic increase in antigen-specific T helper cell proliferation was seen with IL-2 and TNF-alpha gene co-injections. In addition, we observed a significant enhancement of the cytotoxic response with the co-administration of TNF-alpha and IL-15 genes with HIV-1 DNA immunogens. These increases in CTL response were both MHC class I restricted and CD8+ T cell dependent. Together with earlier reports on the utility of co-immunizing using immunologically important molecules together with DNA immunogens, we demonstrate the potential of this strategy as an important tool for the development of more rationally designed vaccines.

Generation and characterization of the humoral immune response to DNA immunization with a chimeric β‐amyloid‐interleukin‐4 minigene

“…Successful DNA immunization with IL-4 as a molecular adjuvant to enhance Th2 type of immune responses to different immunogens has been previously reported [20,21,[35][36][37][38][39]. However, to our knowledge no one examined whether anti-IL-4 antibody production is generated when IL-4 is used as a fusion protein with the immunogen.…”

“…Importantly, it has also been reported that co-administration of IL-4 cytokine gene along with a gene, encoding foreign or "self" antigens, caused the immune response to be driven toward a more Th2-like phenotype [20,21,[35][36][37][38][39]. Here we describe a novel chimeric DNA minigene encoding A g fused with mouse IL-4.…”

Suppression of Immune Response and Protective Immunity to a Japanese Encephalitis Virus DNA Vaccine by Coadministration of an IL-12-Expressing Plasmid

“…To seek an approach to increase the efficacy of the pE DNA vaccine, we tested the use of cytokines as immunological adjuvants. It has been previously demonstrated that the magnitude and nature of the immune responses to DNA vaccines can be regulated by coadministration of a broad panel of cytokine genes (25)(26)(27). Among these cytokine genes, the IL-12 gene promotes Th1 responses and cell-mediated immunity, and the IL-4 gene favors Th2 cell development and production of Abs.…”

Cytokine genetic adjuvant facilitates prophylactic intravascular DNA vaccine against acute and latent herpes simplex virus infection in mice

“…In some reports, the use of cytokine genes brought significant elevation in CTL activities against the antigens. [14][15][16][17]19,21 The results strongly suggest the potential usefulness of the cytokine gene delivery as molecular adjuvants.…”

“…pDNAs encoding interferon (IFN)-g, 14 IL-2, [15][16][17] IL-12, 9,14,[17][18][19][20] 21 IL-18 9,22 and granulocyte-macrophage colony-stimulating factor (GM-CSF) 15,17,19 have been shown to enhance Th1 immune responses triggered by a pDNA vaccine against human immunodeficiency (HIV) virus, [15][16][17]19,21 hepatitis B virus, 14 mycobacterium 20 and HSV, 9,18,22 although the humoral response was elevated 9,[14][15][16][17]19 or downmodulated, 15,18,20,21 depending on the cytokines and antigens employed. In some reports, the use of cytokine genes brought significant elevation in CTL activities against the antigens.…”