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Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104;
Wyeth Lederlie Vaccines, Malvern, PA 19355
IL-12 has been shown to enhance cellular immunity in vitro and in
vivo. Recent reports have suggested that combining DNA vaccine approach
with immune stimulatory molecules delivered as genes may significantly
enhance Ag-specific immune responses in vivo. In particular, IL-12
molecules could constitute an important addition to a herpes vaccine by
amplifying specific immune responses. Here we investigate the utility
of IL-12 cDNA as an adjuvant for a herpes simplex virus-2 (HSV-2) DNA
vaccine in a mouse challenge model. Direct i.m. injection of IL-12 cDNA
induced activation of resting immune cells in vivo. Furthermore,
coinjection with IL-12 cDNA and gD DNA vaccine inhibited both systemic
gD-specific Ab and local Ab levels compared with gD plasmid vaccination
alone. In contrast, Th cell proliferative responses and secretion of
cytokines (IL-2 and IFN-
) and chemokines (RANTES and macrophage
inflammatory protein-1
) were significantly increased by IL-12
coinjection. However, the production of cytokines (IL-4 and IL-10) and
chemokine (MCP-1) was inhibited by IL-12 coinjection. IL-12 coinjection
with a gD DNA vaccine showed significantly better protection from
lethal HSV-2 challenge compared with gD DNA vaccination alone in both
inbred and outbred mice. This enhanced protection appears to be
mediated by CD4+ T cells, as determined by in vivo
CD4+ T cell deletion. Thus, IL-12 cDNA as a DNA vaccine
adjuvant drives Ag-specific Th1 type CD4+ T cell responses
that result in reduced HSV-2-derived morbidity as well as
mortality.
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