title: Efficient modulation of T-cell response by dual-mode, single-carrier delivery of cytokine-targeted siRNA and DNA vaccine to antigen-presenting cells.
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.
authors.affiliation: Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas 78712, USA.
authors.forename: Ankur
authors.initials: A
authors.lastname: Singh
authors.forename: Hui
authors.initials: H
authors.lastname: Nie
authors.forename: Bilal
authors.initials: B
authors.lastname: Ghosn
authors.forename: Hong
authors.initials: H
authors.lastname: Qin
authors.forename: Larry W
authors.initials: LW
authors.lastname: Kwak
authors.forename: Krishnendu
authors.initials: K
authors.lastname: Roy
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism*; D015415:Biomarkers; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D007097:Imines; D019344:Lactic Acid; D051379:Mice; D008807:Mice, Inbred BALB C; D010957:Plasmids / Q000235:genetics; D011095:Polyethylenes; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D034741:RNA, Small Interfering / Q000235:genetics*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology; D019444:Vaccines, DNA / Q000235:genetics* / Q000276:immunology*
chemical_list: D015415:Biomarkers; D016207:Cytokines; D007097:Imines; D011095:Polyethylenes; D034741:RNA, Small Interfering; D019444:Vaccines, DNA; C505405:poly(ethylene imine); D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid