title: Multiple challenges in a mouse model of chemical-induced asthma lead to tolerance: ventilatory and inflammatory responses are blunted, immunologic humoral responses are not.
abstract: To improve our mouse model of chemical-induced asthma we compared a single with a multiple intranasal challenge protocol. BALB/c mice received toluene diisocyanate (TDI) or vehicle on each ear (days 1 and 8) with the first challenge by intranasal instillation given on day 15. In a "long" protocol, the mice received 1 to 6 intranasal instillations, with 1-week interval. In a "short" protocol, the mice received 6 intranasal challenges over a period of 10 days. The "early" ventilatory response and methacholine reactivity were measured. Broncho-alveolar-lavage (BAL), total serum immunoglobulins and draining lymph nodes were analyzed. After 1, 2 or 3 TDI challenges, a significant increase in airway reactivity, total cell count and neutrophils (15-20%) was found in TDI-treated mice. This response diminished with increasing numbers of challenges in both models. The percentage CD4(+) and CD8(+) cells decreased and the percentage CD19(+) cells increased in the lymph nodes, but these returned to control values with multiple challenges. IL-4 secretion increased in cervical lymph node cells in vitro. Total serum IgE levels were persistently increased in TDI-treated mice. Although humoral signs of allergy remain increased after multiple challenges, diminishing ventilatory and inflammatory responses are indicative of the induction of tolerance.
authors.affiliation: Katholieke Universiteit Leuven, Research Unit of Lung Toxicology, Leuven, Belgium. Jeroen.vanoirbeek@med.kuleuven.be
authors.forename: Jeroen A J
authors.initials: JA
authors.lastname: Vanoirbeek
authors.forename: Vanessa
authors.initials: V
authors.lastname: De Vooght
authors.forename: Benoit
authors.initials: B
authors.lastname: Nemery
authors.forename: Peter H M
authors.initials: PH
authors.lastname: Hoet
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects*; D001249:Asthma / Q000139:chemically induced* / Q000276:immunology*; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016085:Bronchoconstrictor Agents; D016207:Cytokines / Q000096:biosynthesis; D007108:Immune Tolerance / Q000187:drug effects*; D007073:Immunoglobulin E / Q000096:biosynthesis; D007074:Immunoglobulin G / Q000096:biosynthesis; D007249:Inflammation / Q000473:pathology*; D008168:Lung / Q000473:pathology; D008198:Lymph Nodes / Q000166:cytology / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D016210:Methacholine Chloride; D051379:Mice; D008807:Mice, Inbred BALB C; D015656:Respiratory Mechanics / Q000187:drug effects*
chemical_list: D016085:Bronchoconstrictor Agents; D016207:Cytokines; D007074:Immunoglobulin G; D016210:Methacholine Chloride; D007073:Immunoglobulin E