Efficient Modulation of T-cell Response by Dual-mode, Single-carrier Delivery of Cytokine-targeted siRNA and DNA Vaccine to Antigen-presenting Cells.

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 γ (IFN-γ) 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.Molecular Therapy (2008) 16 12, 2011–2021 doi:10.1038/mt.2008.206 [ABSTRACT FROM AUTHOR]