title: Expression of tak1 and tram induces synergistic pro-inflammatory signalling and adjuvants DNA vaccines.
abstract: Improving vaccine immunogenicity remains a major challenge in the fight against developing country diseases like malaria and AIDS. We describe a novel strategy to identify new DNA vaccine adjuvants. We have screened components of the Toll-like receptor signalling pathways for their ability to activate pro-inflammatory target genes in transient transfection assays and assessed in vivo adjuvant activity by expressing the activators from the DNA backbone of vaccines. We find that a robust increase in the immune response necessitates co-expression of two activators. Accordingly, the combination of tak1 and tram elicits synergistic reporter activation in transient transfection assays. In a mouse model this combination, but not the individual molecules, induced approximately twofold increases in CD8+ T-cell immune responses. These results indicate that optimal immunogenicity may require activation of distinct innate immune signalling pathways. Thus this strategy offers a novel route to the discovery of a new generation of adjuvants.
authors: The Jenner Institute, University of Oxford, Oxford OX3 7DQ, United Kingdom. karen.colbjorn@googlemail.com
authors: Karen Colbjørn
authors: KC
authors: Larsen
authors: Alexandra J
authors: AJ
authors: Spencer
authors: Anna L
authors: AL
authors: Goodman
authors: Ashley
authors: A
authors: Gilchrist
authors: Julie
authors: J
authors: Furze
authors: Christine S
authors: CS
authors: Rollier
authors: Endre
authors: E
authors: Kiss-Toth
authors: Sarah C
authors: SC
authors: Gilbert
authors: Migena
authors: M
authors: Bregu
authors: Elizabeth J
authors: EJ
authors: Soilleux
authors: Adrian V S
authors: AV
authors: Hill
authors: David H
authors: DH
authors: Wyllie
mesh_terms: D000276:Adjuvants, Immunologic / Q000235:genetics / Q000494:pharmacology*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism*; D019444:Vaccines, DNA / Q000276:immunology*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D000276:Adjuvants, Immunologic; D007371:Interferon-gamma; D020930:MAP Kinase Kinase Kinases; D018123:Receptors, Interleukin; D019444:Vaccines, DNA; D000099151:MAP Kinase Kinase Kinase 7; C476416:Ticam2 protein, mouse