Interleukin-12 redirects murine immune responses to soluble or aluminum phosphate adsorbed HSV-2 glycoprotein D towards Th1 and CD4+ CTL responses |
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| Institution: | 1. Department of Vaccines Discovery Research, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA;2. Department of Viral Vaccine Process Development, Wyeth Research, Pearl River, NY 10965, USA;1. Istanbul University, Cerrahpasa Faculty of Medicine, Department of Radiology, KMPasa, Istanbul, 34098, Turkey;2. Istanbul University, Cerrahpasa Faculty of Medicine, Department of Urology, KMPasa, Istanbul, 34098, Turkey;1. LAQV/Requimte, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Campus de Caparica, 2829-516 Caparica, Portugal;2. LEAF – Linking Landscape, Environment, Agriculture and Food, Instituto Superior de Agronomia, Universidade de Lisboa, Tapada da Ajuda, 1349-017 Lisboa, Portugal;1. LAQV/Requimte, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Campus de Caparica, 2829-516 Caparica, Portugal;2. Laboratory of Membrane Processes, Instituto de Biologia Experimental e Tecnológica (iBET), Apartado 12, 2780-901 Oeiras, Portugal;1. Departamento de Dermatología, Hospital Universitari Joan XXIII, Tarragona, España;2. Departamento de Dermatología, Hospital del Mar, Parc de Salut Mar, Barcelona, España;3. Departamento de Dermatología, Hospital de Viladecans, Viladecans, Barcelona, España;4. Departamento de Anatomía Patológica, Hospital Universitari de Bellvitge, L’Hospitalet del Llobregat, Barcelona, España;1. Center for Health and Medical Psychology (CHAMP), School of Law, Psychology and Social Work, Örebro University, Sweden;2. Department of Psychiatry, School of Medical Sciences, Örebro University, Sweden;3. McLean Hospital & Department of Psychiatry, Harvard Medical School, Boston, USA |
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| Abstract: | 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-γ 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. |
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