title: Oligodeoxynucleotides containing synthetic immunostimulatory motifs augment potent Th1 immune responses to HBsAg in mice.
abstract: Toll-like receptor 9 (TLR9) modulators have potent Th1-adjuvant activity. We recently reported the development of immunomodulatory oligonucleotides (IMOs) containing novel structures (immunomers) and synthetic immunostimulatory CpR (R=2'-deoxy-7-deazguanosine) or R'pG (R'=1-(2'-deoxy-beta-D-ribofuranosyl)-2-oxo-7-deaza-8-methyl-purine) motifs. IMOs activate TLR9 pathways, resulting in cytokine secretion profiles different from those induced by CpG DNA. In the present study we evaluated the adjuvant activity of IMOs containing CpG, CpR, or R'pG motifs in combination with hepatitis B surface antigen (HBsAg) in a mouse model. Mice immunized with HBsAg plus IMO produced higher levels of IgG2a and lower levels of IgG1 than did mice immunized with HBsAg alone or with alum. High IgG2a responses were found at week 4 and remained high until 14 weeks after immunization. Adoptive transfer of splenocytes from HBsAg/IMO-immunized mice to naïve mice resulted in strong IgG2a production in response to antigen boost. Splenocytes of mice immunized with HBsAg/IMO produced high levels of IFN-gamma, but not Th2 cytokines IL-4 and IL-5, in antigen-recall experiments in vitro. The use of IMOs as adjuvants to HBsAg resulted in the production of strong anti-HBsAg antibodies at antigen doses as low as 0.2 microg. These data demonstrate that IMOs enhance the immunogenicity of HBsAg through potent Th1 immune responses, which may allow lower doses of antigen in vaccination.
authors.affiliation: Hybridon, Inc., 345 Vassar Street, Cambridge, MA 02139-4818, United States.
authors.forename: Yukui
authors.initials: Y
authors.lastname: Li
authors.forename: Ekambar R
authors.initials: ER
authors.lastname: Kandimalla
authors.forename: Dong
authors.initials: D
authors.lastname: Yu
authors.forename: Sudhir
authors.initials: S
authors.lastname: Agrawal
mesh_terms: D000276:Adjuvants, Immunologic / Q000235:genetics*; D000536:Aluminum Hydroxide / Q000494:pharmacology; D020816:Amino Acid Motifs; D000818:Animals; D017690:Cell Transplantation; D002478:Cells, Cultured; D018899:CpG Islands / Q000235:genetics; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006514:Hepatitis B Surface Antigens / Q000276:immunology*; D007156:Immunologic Memory; D051379:Mice; D008807:Mice, Inbred BALB C; D009841:Oligonucleotides / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics; D013154:Spleen / Q000166:cytology; D018417:Th1 Cells / Q000276:immunology*; D051217:Toll-Like Receptor 9
chemical_list: D000276:Adjuvants, Immunologic; D004268:DNA-Binding Proteins; D006514:Hepatitis B Surface Antigens; D009841:Oligonucleotides; D011956:Receptors, Cell Surface; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D000536:Aluminum Hydroxide; D004247:DNA