title: Modulation of plasmid DNA vaccine antigen clearance by caspase 12 RNA interference potentiates vaccination.
abstract: The magnitude of the immune responses elicited by plasmid DNA vaccines might be limited, in part, by the duration of vaccine antigen expression in vivo. To explore strategies for improving plasmid DNA vaccine efficacy, we studied the apoptotic process in myocytes of mice vaccinated intramuscularly. We found that after vaccination, the proapoptotic protein caspase 12 (Casp12) was upregulated in myocytes coincident with the loss of vaccine antigen expression. To harness this observation to improve plasmid DNA vaccine efficacy, we used RNA interference technology, coadministering plasmid DNA expressing a short hairpin RNA (shRNA) of Casp12 with plasmid DNA vaccine constructs. This treatment with shRNA Casp12, administered twice within the first 10 days following vaccine administration, increased antigen expression 7-fold, the antigen-specific CD8(+) T cell immune response 6-fold, and antigen-specific antibody production 5-fold. This study demonstrates the critical role for Casp12 in plasmid DNA vaccine-induced immune responses and shows that increased antigen expression mediated by down-modulation of Casp12 can be used to potentiate vaccine efficacy.
authors.affiliation: Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center and Harvard Medical School, 3 Blackfan Circle, Center for Life Science, Boston, MA 02115, USA. acceleration@rcn.com
authors.forename: Ralf
authors.initials: R
authors.lastname: Geiben-Lynn
authors.forename: Kwesi
authors.initials: K
authors.lastname: Frimpong-Boateng
authors.forename: Norman L
authors.initials: NL
authors.lastname: Letvin
mesh_terms: D000818:Animals; D000906:Antibodies / Q000097:blood; D000941:Antigens / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D053454:Caspase 12; D061945:Caspase Inhibitors; D007273:Injections, Intramuscular; D051379:Mice; D008810:Mice, Inbred C57BL; D032342:Muscle Cells / Q000502:physiology; D010957:Plasmids / Q000008:administration & dosage; D034622:RNA Interference; D014611:Vaccination / Q000379:methods*; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*
chemical_list: D000906:Antibodies; D000941:Antigens; D061945:Caspase Inhibitors; D019444:Vaccines, DNA; C506440:Casp12 protein, mouse; D053454:Caspase 12