title: Presentation of proteins encapsulated in sterically stabilized liposomes by dendritic cells initiates CD8(+) T-cell responses in vivo.
abstract: Liposomes have been proposed as a vehicle to deliver proteins to antigen-presenting cells (APC), such as dendritic cells (DC), to stimulate strong T cell-mediated immune responses. Unfortunately, because of their instability in vivo and their rapid uptake by cells of the mononuclear phagocyte system on intravenous administration, most types of conventional liposomes lack clinical applicability. In contrast, sterically stabilized liposomes (SL) have increased in vivo stability. It is shown that both immature and mature DC take up SL into neutral or mildly acidic compartments distinct from endocytic vacuoles. These DC presented SL-encapsulated protein to both CD4(+) and CD8(+) T cells in vitro. Although CD4(+) T-cell responses were comparable to those induced by soluble protein, CD8(+) T-cell proliferation was up to 300-fold stronger when DC had been pulsed with SL-encapsulated ovalbumin. DC processed SL-encapsulated antigen through a TAP-dependent mechanism. Immunization of mice with SL-encapsulated ovalbumin led to antigen presentation by DC in vivo and stimulated greater CD8(+) T-cell responses than immunization with soluble protein or with conventional or positively charged liposomes carrying ovalbumin. Therefore, the application of SL-encapsulated antigens offers a novel effective, safe vaccine approach if a combination of CD8(+) and CD4(+) T-cell responses is desired (ie, in anti-viral or anti-tumor immunity).
authors.affiliation: Laboratory of Cellular Physiology and Immunology and the Aaron Diamond AIDS Research Center, Rockefeller University, New York, NY, USA.
authors.forename: R
authors.initials: R
authors.lastname: Ignatius
authors.forename: K
authors.initials: K
authors.lastname: Mahnke
authors.forename: M
authors.initials: M
authors.lastname: Rivera
authors.forename: K
authors.initials: K
authors.lastname: Hong
authors.forename: F
authors.initials: F
authors.lastname: Isdell
authors.forename: R M
authors.initials: RM
authors.lastname: Steinman
authors.forename: M
authors.initials: M
authors.lastname: Pope
authors.forename: L
authors.initials: L
authors.lastname: Stamatatos
mesh_terms: D019264:Adoptive Transfer / Q000379:methods / Q000592:standards; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D004339:Drug Compounding / Q000379:methods / Q000592:standards; D016503:Drug Delivery Systems / Q000592:standards; D004355:Drug Stability; D005456:Fluorescent Dyes; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008198:Lymph Nodes / Q000166:cytology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology; D011506:Proteins / Q000008:administration & dosage / Q000276:immunology* / Q000494:pharmacology; D013744:Tetanus Toxin / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology
chemical_list: D005456:Fluorescent Dyes; D008081:Liposomes; D011506:Proteins; D013744:Tetanus Toxin; D010047:Ovalbumin