Interleukin-12 redirects murine immune responses to soluble or aluminum phosphate adsorbed HSV-2 glycoprotein D towards Th1 and CD4+ CTL responses.
The type of immune response elicited against HSV-2 infection may be a factor in the frequency and severity of recurrent disease, with non-recurrent status being associated with a Th1-like response. As administration of glycoprotein D subunit formulated with an aluminum-based adjuvant induces predominantly Th2-like immune responses, we sought to assess the ability of IL-12 to redirect anti-HSV immunity towards a Th1 response. Co-administration of gD with IL-12 resulted in gD-specific antibody subclass switching from predominantly IgG1 observed in mice immunized with either gD or gD/AlPO4 to a more balanced combination of IgG1 and IgG2a, and enhanced virus neutralizing activity. Spleen cells from mice immunized with gD and IL-12, and restimulated in vitro with HSV-2, developed into effector cells capable of secreting IFN-gamma and lysing HSV-2 infected targets, while those obtained from gD or gD/ALPO4 immunized mice did not express lytic activity. In vitro studies determined that these CTLs were CD4+ and that the cytotoxicity was primarily perforin dependent. Vaginal challenge with HSV-2 demonstrated that IL-12 co-administration with gD resulted in increased efficacy of this vaccine as compared to administration of gD antigen alone. This acquired protection persisted up to 1 year. Finally, adsorbing gD and IL-12 to AlPO4 decreased the optimal dose of IL-12 required to enhance gD immunogenicity and shift responses towards a Th1-like profile.
Cooper
David
D
Department of Vaccines Discovery Research, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA.
Pride
Michael W
MW
Guo
Min
M
Cutler
Mark
M
Mester
Joseph C
JC
Nasar
Farooq
F
She
Jian
J
Souza
Victor
V
York
Laura
L
Mishkin
Eric
E
Eldridge
John
J
Natuk
Robert J
RJ
D000276:Adjuvants, Immunologic; D017607:Aluminum Compounds / Q000737:chemistry*; D000818:Animals; D000906:Antibodies / Q000737:chemistry; D004195:Disease Models, Animal; D006561:Herpes Simplex / Q000276:immunology / Q000517:prevention & control; D018258:Herpesvirus 2, Human / Q000276:immunology; D006801:Humans; D007109:Immunity / Q000187:drug effects*; D018664:Interleukin-12 / Q000276:immunology / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010710:Phosphates / Q000737:chemistry*; D012995:Solubility / Q000187:drug effects; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology
D000276:Adjuvants, Immunologic; D017607:Aluminum Compounds; D000906:Antibodies; D010710:Phosphates; D018664:Interleukin-12; C012714:aluminum phosphate