A Dual-Function DNA Vaccine Encoding Carcinoembryonic Antigen and CD40 Ligand Trimer Induces T Cell-Mediated Protective Immunity Against Colon Cancer in Carcinoembryonic Antigen-Transgenic Mice
| Autor: | Andreas G. Niethammer, Rong Xiang, Ralph A. Reisfeld, Steve Silletti, F. James Primus, Carrie S. Dolman, Stephen D. Gillies, Holger N. Lode, J. Michael Ruehlmann |
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| Rok vydání: | 2001 |
| Předmět: |
Recombinant Fusion Proteins
T cell CD40 Ligand Immunology Mice Transgenic Cancer Vaccines DNA vaccination Mice Carcinoembryonic antigen Antigen Antigens CD Antigens Neoplasm Vaccines DNA medicine Animals Immunology and Allergy IL-2 receptor CD86 Membrane Glycoproteins CD40 biology Carcinoma Vaccination Epithelial Cell Adhesion Molecule Molecular biology Carcinoembryonic Antigen medicine.anatomical_structure Colonic Neoplasms B7-1 Antigen biology.protein Interleukin-2 B7-2 Antigen Cell Adhesion Molecules CD80 T-Lymphocytes Cytotoxic |
| Zdroj: | The Journal of Immunology. 167:4560-4565 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.167.8.4560 |
| Popis: | A carcinoembryonic Ag (CEA)-based DNA vaccine encoding both CEA and CD40 ligand trimer achieved effective tumor-protective immunity against murine colon carcinoma in CEA-transgenic mice by activating both naive T cells and dendritic cells. Peripheral T cell tolerance to CEA was broken in a prophylactic model by this novel, dual-function DNA vaccine, whose efficacy was further enhanced by boosts with a recombinant Ab-IL-2 fusion protein (huKS1/4-IL-2). These conclusions are supported by four lines of evidence. First, a lethal challenge of MC38-CEA-KS Ag murine colon carcinoma cells was for the first time completely rejected in 100% of experimental animals treated by oral gavage of this DNA vaccine carried by attenuated Salmonella typhimurium, followed by five boosts with huKS1/4-IL-2. Second, specific activation of dendritic cells was indicated by their marked up-regulation in expression of costimulatory molecules B7.1 (CD80), B7.2 (CD86), and ICAM-1. Third, a decisive increase over control values was observed in both MHC class I Ag-restricted cytotoxicity of CTLs from successfully vaccinated mice and secretion of proinflammatory cytokines IFN-γ and IL-12. Fourth, activation of CTLs was augmented, as indicated by up-regulation of activity markers LFA-1, CD25, CD28, and CD69. Taken together, these results suggest that a dual-function DNA vaccine encoding CEA and CD40 ligand trimer combined with tumor-targeted IL-2 may be a promising strategy for the rational development of DNA-based cancer vaccines for future clinical applications. |
| Databáze: | OpenAIRE |
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