Enhancement of protective humoral (Th2) and cell-mediated (Th1) immune responses against herpes simplex virus-2 through co-delivery of granulocyte-macrophage colony-stimulating factor expression cassettes

Abstract

Granulocyte-macrophage colony-stimulating factor (GM-CSF) could in theory attract antigen-presenting cells in muscle following intramuscular DNA immunization, resulting in enhanced antigen-specific immune responses. Thus, such adjuvants could constitute an important addition to a herpes vaccine by amplifying specific immune responses. Here we investigate the utility of GM-CSF cDNA as a vaccine adjuvant for herpes simplex virus (HSV)-2 in a mouse challenge model. GM-CSF cDNA co-injection enhanced levels of specific IgG, IgE and IgA against HSV-2 gD protein significantly higher than gD plasmid vaccination alone. Moreover, GM-CSF co-injection induced a dramatic increase in IgG1 levels, as compared to IgG2a levels, suggesting a Th2 bias in the response. T helper cell proliferation and secretion of cytokines (IL-2 and IFN-+ ) were significantly increased by GM-CSF cDNA co-injection. When challenged with a lethal dose of HSV-2, GM-CSF co-injection increased survival rates to 90 %, an improvement as compared to gD vaccination alone (60-63 %). Furthermore, GM-CSF cDNA co-injection reduced herpetic lesions and resulted in a faster recovery from lesions. These data indicate that GM-CSF cDNA enhances both humoral and cellular immune responses and enhances vaccine efficacy, resulting in reduced HSV-2-derived morbidity as well as mortality.

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

“…Most groups concluded that GM-CSF could activate both Th1 and Th2 immune responses whereas others reported that GM-CSF biased immune response toward either a Th1 or a Th2 response. [13][14][15] Moreover, Kusakabe et al 19 demonstrated that the timing of GM-CSF expression in the context of plasmid administration influenced the Th1/Th2 response. 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.…”

“…10 The adjuvant activity of GM-CSF has been demonstrated in several models with antigens that generally have a low immunogenicity. [11][12][13] GM-CSF has been reported to increase both humoral and cellular immune responses, 14,15 as well as to skew the Th1/Th2 balance. It is well accepted that GM-CSF acts as an adjuvant to enhance the immune response against the target antigen of interest; however, the ultimate effects of GM-CSF are not fully understood.…”

Induction of Protective Immunity againstSchistosoma mansonivia DNA Priming and Boosting with the Large Subunit of Calpain (Sm-p80): Adjuvant Effects of Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin-4

“…Therefore, it is logical that linking antigen and GM-CSF expression closely in vivo may provide a more conducive microenvironment for the uptake and presentation of antigen by dendritic cells or macrophages (53). Similarly, plasmids coding for IL-4 have also been used to preferentially augment B-cellmediated Th2 responses and Ig class switching (15,16,49).…”

Safety of a GM-CSF adjuvant-plasmid DNA malaria vaccine

“…The human GM-CSF pDNA was included in the vaccine to increase the immunogenicity as GM-CSF is known to attract dendritic cells to the site of administration and enhance the maturation of dendritic cell precursors which play an important role in antigen presentation. [19][20][21][22][23][24] While co-administration of GM-CSF pDNA has been demonstrated to enhance the immunogenicity of pDNA vaccines, [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] the overexpression of GM-CSF in transgenic mice has been demonstrated to result in adverse pathology associated with overaccumulation of macrophages in tissues, accumulation of macrophages in the peritoneal and pleural cavities, retinal damage, muscle wasting, and a fatal tissue damage syndrome. 37 Thus, the inclusion of GM-CSF in the vaccine raised several important theoretical safety concerns which had to be addressed before the vaccine could be taken into a clinical trial with healthy volunteers.…”