title: Requirement of MyD88 and Fas pathways for the efficacy of allergen-free immunotherapy.
abstract: BACKGROUND
  We have shown that mycobacterial antigens and CpG oligodeoxynucleotides downmodulate airway allergic inflammation by mechanisms dependent on T-cell activation. Here, we investigated the participation of the innate response, particularly the role of MyD88 adaptor, and Fas molecules in the effectiveness of DNA-HSP65 or CpG/culture filtrated proteins (CFP) immunotherapy.
  
  
  METHODS
  Mice sensitized and challenged with Der p 1 allergen were treated with DNA-HSP65, CpG/CFP, or with adoptively transferred cells from immunized mice. The treatment efficacy was assessed by evaluating eosinophil recruitment, antibody, and cytokine production.
  
  
  RESULTS
  In addition to downregulating the Th2 response, DNA-HSP65 and CpG/CFP promoted IL-10 and IFN-γ production. Adoptive transfer of cells from mice immunized with DNA-HSP65 or CpG/CFP to allergic recipients downmodulated the allergic response. Notably, transfer of cells from DNA-HSP65- or CpG/CFP-immunized MyD88(-/-) mice failed to reduce allergy. Additionally, for effective reduction of allergy by cells from CpG/CFP-immunized mice, Fas molecules were required. Although DNA-HSP65 or CpG/CFP immunization stimulated antigen-specific production of IFN-γ and IL-10, the effect of DNA-HSP65 was associated with IL-10 while CpG/CFP was associated with IFN-γ. Moreover, after stimulation with mycobacterial antigens plus Der p 1 allergen, cells from mite-allergic patients with asthma exhibited similar patterns of cytokine production as those found in the lung of treated mice.
  
  
  CONCLUSIONS
  This study provides new insights on the mechanisms of allergen-free immunotherapy by showing that both DNA-HSP65 and CpG/CFP downregulated house dust mite-induced allergic airway inflammation via distinct pathways that involve not only induction of mycobacterial-specific adaptive responses but also signaling via MyD88 and Fas molecules.
authors.affiliation: Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: D M
authors.initials: DM
authors.lastname: Fonseca
authors.forename: P F
authors.initials: PF
authors.lastname: Wowk
authors.forename: M O
authors.initials: MO
authors.lastname: Paula
authors.forename: A F
authors.initials: AF
authors.lastname: Gembre
authors.forename: M D
authors.initials: MD
authors.lastname: Baruffi
authors.forename: M L
authors.initials: ML
authors.lastname: Fermino
authors.forename: W M
authors.initials: WM
authors.lastname: Turato
authors.forename: L W
authors.initials: LW
authors.lastname: Campos
authors.forename: C L
authors.initials: CL
authors.lastname: Silva
authors.forename: S G
authors.initials: SG
authors.lastname: Ramos
authors.forename: C
authors.initials: C
authors.lastname: Horn
authors.forename: G
authors.initials: G
authors.lastname: Marchal
authors.forename: L K
authors.initials: LK
authors.lastname: Arruda
authors.forename: M
authors.initials: M
authors.lastname: Russo
authors.forename: V L D
authors.initials: VL
authors.lastname: Bonato
mesh_terms: D000485:Allergens / Q000276:immunology; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D039741:Antigens, Dermatophagoides / Q000276:immunology; D060829:Arthropod Proteins / Q000276:immunology; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D003546:Cysteine Endopeptidases / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004804:Eosinophils / Q000276:immunology; D005260:Female; D006801:Humans; D006967:Hypersensitivity / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000628:therapy; D007167:Immunotherapy; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009161:Mycobacterium / Q000276:immunology; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D039981:Pyroglyphidae / Q000276:immunology; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
chemical_list: D000485:Allergens; D000942:Antigens, Bacterial; D039741:Antigens, Dermatophagoides; D060829:Arthropod Proteins; C408982:CPG-oligonucleotide; D016207:Cytokines; D053594:Myeloid Differentiation Factor 88; D009838:Oligodeoxyribonucleotides; D019014:fas Receptor; D003546:Cysteine Endopeptidases; C451162:Dermatophagoides pteronyssinus antigen p 1
keywords: CpG oligodeoxynucleotides; allergen-free immunotherapy; experimental allergy; mycobacterial antigens