title: Adjuvant activities of immune response modifier R-848: comparison with CpG ODN.
abstract: R-848 and imiquimod belong to a class of immune response modifiers that are potent inducers of cytokines, including IFN-alpha, TNF-alpha, IL-12, and IFN-gamma. Many of these cytokines can affect the acquired immune response. This study examines the effects of R-848 on aspects of acquired immunity, including immunoglobulin secretion, in vivo cytokine production, and Ag-specific T cell cytokine production. Results are compared with those of Th1 CpG ODN. R-848 and CpG ODN are effective at skewing immunity in the presence of Alum toward a Th1 Ab response (IgG2a) and away from a Th2 Ab response (IgE). R-848 and CpG ODN are also capable of initiating an immune response in the absence of additional adjuvant by specifically enhancing IgG2a levels. Both R-848 and imiquimod showed activity when given subcutaneously or orally, indicating that the compound mechanism was not through generation of a depot effect. Although CpG ODN behaves similarly to R-848, CpG ODN has a distinct cytokine profile, is more effective than R-848 when given with Alum in the priming dose, and is active only when given by the same route as the Ag. The mechanism of R-848's adjuvant activity is linked to cytokine production, where increases in IgG2a levels are associated with IFN-alpha, TNF-alpha, IL-12, and IFN-gamma induction, and decreases in IgE levels are associated with IFN-alpha and TNF-alpha. Imiquimod also enhances IgG2a production when given with Ag. The above results suggest that the imidazoquinolines R-848 and imiquimod may be attractive compounds for use as vaccine adjuvants and in inhibiting pathological responses mediated by Th2 cytokines.
authors.affiliation: Department of Pharmacology, 3M Pharmaceuticals, St. Paul, Minnesota 55144, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Vasilakos
authors.forename: R M
authors.initials: RM
authors.lastname: Smith
authors.forename: S J
authors.initials: SJ
authors.lastname: Gibson
authors.forename: J M
authors.initials: JM
authors.lastname: Lindh
authors.forename: L K
authors.initials: LK
authors.lastname: Pederson
authors.forename: M J
authors.initials: MJ
authors.lastname: Reiter
authors.forename: M H
authors.initials: MH
authors.lastname: Smith
authors.forename: M A
authors.initials: MA
authors.lastname: Tomai
mesh_terms: D000276:Adjuvants, Immunologic; D000284:Administration, Oral; D000818:Animals; D002469:Cell Separation; D016207:Cytokines / Q000032:analysis; D005260:Female; D007093:Imidazoles / Q000276:immunology*; D007117:Immunization, Secondary; D007073:Immunoglobulin E / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000276:immunology*; D010047:Ovalbumin / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014611:Vaccination
chemical_list: D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D016207:Cytokines; D007093:Imidazoles; D007074:Immunoglobulin G; D009838:Oligodeoxyribonucleotides; D007073:Immunoglobulin E; D007371:Interferon-gamma; D010047:Ovalbumin; C402365:resiquimod