1. Efficient modulation of T-cell response by dual-mode, single-carrier delivery of cytokine-targeted siRNA and DNA vaccine to antigen-presenting cells.
- Author
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Singh A, Nie H, Ghosn B, Qin H, Kwak LW, and Roy K
- Subjects
- Animals, Biomarkers, Bone Marrow immunology, Bone Marrow metabolism, Cell Proliferation, Cells, Cultured, Cytokines genetics, Dendritic Cells immunology, Dendritic Cells metabolism, Female, Gene Expression Regulation, Imines, Lactic Acid, Mice, Mice, Inbred BALB C, Plasmids genetics, Polyethylenes, Polyglycolic Acid, Polylactic Acid-Polyglycolic Acid Copolymer, T-Lymphocytes cytology, T-Lymphocytes metabolism, Up-Regulation immunology, Antigen-Presenting Cells immunology, Antigen-Presenting Cells metabolism, Cytokines immunology, RNA, Small Interfering genetics, T-Lymphocytes immunology, Vaccines, DNA genetics, Vaccines, DNA immunology
- Abstract
Controlled modulation of T-cell response during immunotherapy, especially the balance between T helper 1 (Th1) and Th2 responses, is critical for generating effective immune response. Here we report that dual delivery of interleukin 10 (IL-10)-targeted small interfering RNA (siRNA) and DNA vaccines to dendritic cells (DCs), using a single particle carrier, efficiently enhances immune response and modulates it toward a stronger Th1 phenotype. Surface-functionalized polymer microparticles (MPs) carrying both IL-10-targeted siRNA and DNA antigens exhibited effective gene silencing, DNA transfection, and synergistically enhanced upregulation of maturation markers in primary DCs leading to increased T-cell proliferation, in vitro. Mice immunized with these dual-delivery carriers demonstrated a significant "switch" toward Th1 response as evidenced by increase in interferon gamma (IFN-gamma) production and decrease in IL-4 production by CD4+ T cells. This further led to enhanced antiviral cytotoxic T-lymphocyte activity. Such dual siRNA-DNA delivery provides a novel strategy to precisely control the type and strength of T-cell response during immunotherapy.
- Published
- 2008
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