Paracrine Release of IL-12 Stimulates IFN-γ Production and Dramatically Enhances the Antigen-Specific T Cell Response after Vaccination with a Novel Peptide-Based Cancer Vaccine
| Autor: | Andre N. Kadima, Marina Demcheva, David J. Cole, William E. Gillanders, Christophe L. Nguyen, Mark P. Rubinstein, Mohamed L. Salem, Yuehua Zhou, John N. Vournakis |
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| Rok vydání: | 2004 |
| Předmět: |
Ovalbumin
medicine.medical_treatment T cell Immunology Melanoma Experimental Antigen-Presenting Cells Epitopes T-Lymphocyte Mice Transgenic CD8-Positive T-Lymphocytes Cancer Vaccines Interferon-gamma Mice Paracrine signalling Immune system Adjuvants Immunologic T-Lymphocyte Subsets Cell Line Tumor Paracrine Communication medicine Animals Immunology and Allergy business.industry Egg Proteins Receptors Interleukin-12 Receptors Interleukin Adoptive Transfer Interleukin-12 Peptide Fragments Mice Inbred C57BL medicine.anatomical_structure Cytokine Vaccines Subunit Systemic administration Cancer research Cancer vaccine business Gels Immunologic Memory Adjuvant Memory T cell |
| Zdroj: | The Journal of Immunology. 172:5159-5167 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.172.9.5159 |
| Popis: | 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-γ−/− and IL-12Rβ2−/− 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. |
| Databáze: | OpenAIRE |
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