title: IFN-γ-mediated efficacy of allergen-free immunotherapy using mycobacterial antigens and CpG-ODN.
abstract: Epidemiological and experimental evidence supports the notion that microbial infections that are known to induce Th1-type immune responses can suppress Th2 immune responses, which are characteristics of allergic disorders. However, live microbial immunization might not be feasible for human immunotherapy. Here, we evaluated whether induction of Th1 immunity by the immunostimulatory sequences of CpG-oligodeoxynucleotides (CpG-ODN), with or without culture filtrate proteins (CFP), from Mycobacterium tuberculosis would suppress ongoing allergic lung disease. Presensitized and ovalbumin (OVA)-challenged mice were treated subcutaneously with CpG, or CpG in combination with CFP (CpG/CFP). After 15 days of treatment, airway inflammation and specific T- and B-cell responses were determined. Cell transfer experiments were also performed. CpG treatment attenuated airway allergic disease; however, the combination CpG/CFP treatment was significantly more effective in decreasing airway hyperresponsiveness, eosinophilia and Th2 response. When an additional intranasal dose of CFP was given, allergy was even more attenuated. The CpG/CFP therapy also reduced allergen-specific IgG1 and IgE antibodies and increased IgG2a. Transfer of spleen cells from mice immunized with CpG/CFP also reduced allergic lung inflammation. CpG/CFP treatment induced CFP-specific production of IFN-γ and IL-10 by spleen cells and increased production of IFN-γ in response to OVA. The essential role of IFN-γ for the therapeutic effect of CpG/CFP was evidenced in IFN-γ knockout mice. These results show that CpG/CFP treatment reverses established Th2 allergic responses by an IFN-γ-dependent mechanism that seems to act both locally in the lung and systemically to decrease allergen-specific Th2 responses.
authors.affiliation: Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Riberão Preto, Brazil.
authors.forename: Denise M
authors.initials: DM
authors.lastname: Fonseca
authors.forename: Marina O
authors.initials: MO
authors.lastname: Paula
authors.forename: Pryscilla F
authors.initials: PF
authors.lastname: Wowk
authors.forename: Lívia W
authors.initials: LW
authors.lastname: Campos
authors.forename: Ana F
authors.initials: AF
authors.lastname: Gembre
authors.forename: Walter M
authors.initials: WM
authors.lastname: Turato
authors.forename: Simone G
authors.initials: SG
authors.lastname: Ramos
authors.forename: Marcelo
authors.initials: M
authors.lastname: Dias-Baruffi
authors.forename: Renato
authors.initials: R
authors.lastname: Barboza
authors.forename: Eliane
authors.initials: E
authors.lastname: Gomes
authors.forename: Cynthia
authors.initials: C
authors.lastname: Horn
authors.forename: Gilles
authors.initials: G
authors.lastname: Marchal
authors.forename: Luisa K
authors.initials: LK
authors.lastname: Arruda
authors.forename: Momtchilo
authors.initials: M
authors.lastname: Russo
authors.forename: Vânia L D
authors.initials: VL
authors.lastname: Bonato
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology* / Q000494:pharmacology / Q000627:therapeutic use; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016207:Cytokines / Q000096:biosynthesis; D004802:Eosinophilia / Q000188:drug therapy; D005260:Female; D006967:Hypersensitivity / Q000276:immunology / Q000628:therapy*; D007073:Immunoglobulin E / Q000096:biosynthesis; D007074:Immunoglobulin G / Q000096:biosynthesis; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology*; D016753:Interleukin-10 / Q000096:biosynthesis; D008171:Lung Diseases / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000276:immunology* / Q000627:therapeutic use*; D010047:Ovalbumin / Q000276:immunology; D013154:Spleen / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D000942:Antigens, Bacterial; C408982:CPG-oligonucleotide; D016207:Cytokines; D007074:Immunoglobulin G; D009838:Oligodeoxyribonucleotides; D016753:Interleukin-10; D007073:Immunoglobulin E; D007371:Interferon-gamma; D010047:Ovalbumin