title: The neonatal susceptibility window for inhalant allergen sensitization in the atopically predisposed canine asthma model.
abstract: Allergic asthma often begins in early life and, although many risk factors have been enumerated, the specific factors that initiate disease progression in an individual remain unclear. Using our dog model of early life allergen inhalation, we tested the hypothesis that the atopically biased neonatal immune system would exhibit tolerance to ragweed if allowed to mature normally before exposure or artificially through innate immune stimulation with early life exposure. Dogs were subjected to a series of inhalational ragweed exposures from 1 to 20 weeks old, with or without inhalation of a Toll-like receptor 4 (TLR4) agonist (CRX-527), or from 13 to 31 weeks old. Serum allergen-specific antibody response was assessed at 4, 8 and 20 weeks after the last sensitizing exposure. At 24 or 35 weeks old, airway hyper-responsiveness to methacholine and ragweed challenges and pulmonary inflammation by bronchoalveolar lavage were tested 1 and 4 days after ragweed challenge at 28 or 39 weeks old. Allergen-free immune maturation resulted in no airway hyper-responsiveness and very little ragweed-specific IgE relative to the control group, but eosinophilia developed upon ragweed challenge. TLR4 agonism yielded no airway hyper-responsiveness, but a strong airway neutrophilia developed upon ragweed challenge. Our data indicate that an atopic predisposition creates a critical window in which allergen exposure can lead to an asthmatic phenotype. Allergen-free immune maturation may lead to allergen tolerance. TLR4 agonism before early life allergen exposure may abrogate the development of allergen-specific bronchonconstriction, but allergen-specific pulmonary inflammation remains a strong concern.
authors.affiliation: Respiratory Immunology and Asthma Program, Lovelace Respiratory Research Institute, Albuquerque, NM 87108, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Royer
authors.forename: Karin
authors.initials: K
authors.lastname: Rudolph
authors.forename: Edward G
authors.initials: EG
authors.lastname: Barrett
mesh_terms: D000280:Administration, Inhalation; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology; D031164:Ambrosia / Q000276:immunology; D000818:Animals; D000831:Animals, Newborn; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D016084:Bronchoconstriction / Q000187:drug effects / Q000276:immunology; D003888:Desensitization, Immunologic; D004285:Dogs; D004802:Eosinophilia / Q000276:immunology / Q000473:pathology; D005260:Female; D005944:Glucosamine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D007108:Immune Tolerance / Q000187:drug effects*; D007073:Immunoglobulin E / Q000097:blood; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use*; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D016210:Methacholine Chloride / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000276:immunology
chemical_list: C530112:AGP 527; D000485:Allergens; D007155:Immunologic Factors; D009943:Organophosphorus Compounds; D051197:Toll-Like Receptor 4; D016210:Methacholine Chloride; D007073:Immunoglobulin E; D005944:Glucosamine