title: Paracrine release of IL-12 stimulates IFN-gamma production and dramatically enhances the antigen-specific T cell response after vaccination with a novel peptide-based cancer vaccine.
abstract: Interleukin-12 can act as a potent adjuvant for T cell vaccines, but its clinical use is limited by toxicity. Paracrine administration of IL-12 could significantly enhance the response to such vaccines without the toxicity associated with systemic administration. We have developed a novel vaccine delivery system (designated F2 gel matrix) composed of poly-N-acetyl glucosamine that has the dual properties of a sustained-release delivery system and a potent adjuvant. To test the efficacy of paracrine IL-12, we incorporated this cytokine into F2 gel matrix and monitored the response of OT-1 T cells in an adoptive transfer model. Recipient mice were vaccinated with F2 gel/SIINFEKL, F2 gel/SIINFEKL/IL-12 (paracrine IL-12), or F2 gel/SIINFEKL plus systemic IL-12 (systemic IL-12). Systemic levels of IL-12 were lower in paracrine IL-12-treated mice, suggesting that paracrine administration of IL-12 may be associated with less toxicity. However, paracrine administration of IL-12 was associated with an enhanced Ag-specific T cell proliferative and functional response. Furthermore, paracrine IL-12 promoted the generation of a stable, functional memory T cell population and was associated with protection from tumor challenge. To study the mechanisms underlying this enhanced response, wild-type and gene-deficient mice were used. The enhanced immune response was significantly reduced in IFN-gamma(-/-) and IL-12R beta 2(-/-) recipient mice suggesting that the role of IL-12 is mediated, at least in part, by host cells. Collectively, the results support the potential of F2 gel matrix as a vaccine delivery system and suggest that sustained paracrine release of IL-12 has potential clinical application.
authors.affiliation: Department of Surgery, Section of Surgical Oncology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Mohamed L
authors.initials: ML
authors.lastname: Salem
authors.forename: Andre N
authors.initials: AN
authors.lastname: Kadima
authors.forename: Yuehua
authors.initials: Y
authors.lastname: Zhou
authors.forename: Christophe L
authors.initials: CL
authors.lastname: Nguyen
authors.forename: Mark P
authors.initials: MP
authors.lastname: Rubinstein
authors.forename: Marina
authors.initials: M
authors.lastname: Demcheva
authors.forename: John N
authors.initials: JN
authors.lastname: Vournakis
authors.forename: David J
authors.initials: DJ
authors.lastname: Cole
authors.forename: William E
authors.initials: WE
authors.lastname: Gillanders
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000378:metabolism / Q000502:physiology; D019264:Adoptive Transfer; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000637:transplantation; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D045744:Cell Line, Tumor; D004527:Egg Proteins / Q000008:administration & dosage / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000276:immunology*; D005782:Gels; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000502:physiology; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics; D008546:Melanoma, Experimental / Q000276:immunology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D019899:Paracrine Communication / Q000276:immunology; D010446:Peptide Fragments; D018123:Receptors, Interleukin / Q000096:biosynthesis; D053707:Receptors, Interleukin-12; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D004527:Egg Proteins; D018984:Epitopes, T-Lymphocyte; D005782:Gels; C110366:OVA-8; D010446:Peptide Fragments; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D022223:Vaccines, Subunit; D018664:Interleukin-12; D007371:Interferon-gamma; D010047:Ovalbumin