dinitrobenzenes and Asthma

Occupational exposure to chemicals is an important cause of asthma. Recent studies indicate that IgE antibodies enhance sensitization to chemicals in the skin.. We investigated whether IgE might similarly promote the development of airway inflammation following inhalation of a contact sensitizer.. A model of chemical-induced asthma is described in which introduction of the low-molecular-weight compound, trinitrobenzene sulphonic acid (TNBS), via the respiratory tract was used for both sensitization and challenge. The role of IgE antibodies in the immune response to inhaled TNBS in this model was assessed by comparing the responses of wild-type (WT) and IgE-deficient (IgE(-/-)) mice on the BALB/c background. Reconstitution of circulating IgE levels by intravenous injection of IgE antibodies into IgE(-/-) mice before sensitization was performed to confirm the role of IgE in any differences observed between the responses of WT and IgE(-/-) mice.. Intranasal challenge of TNBS-sensitized (but not sham-sensitized control mice) induced intense pulmonary inflammation. Macrophages, eosinophils and lymphocytes, including T, B, natural killer and natural killer T cells, were recruited to the airway and the animals displayed bronchial hyperresponsiveness (BHR) to methacholine. Serum levels of murine mast cell protease-1 (mMCP-1) were elevated suggesting mast cell activation. In contrast, the development of airway inflammation, recruitment of lymphocytes, induction of BHR and production of mMCP-1 were all significantly attenuated in IgE-deficient mice. Reconstitution of IgE(-/-) mice with IgE (of unrelated antigen specificity) before sensitization partially restored these features of asthma.. Our data indicate that IgE antibodies non-specifically enhance the development of airway inflammation induced by exposure to chemical antigens.

Topics: Airway Resistance; Animals; Asthma; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Cell Count; Chemokine CCL2; Dinitrobenzenes; Disease Models, Animal; Eosinophils; Haptens; Immunization; Immunoglobulin E; Inflammation; Killer Cells, Natural; Lung; Metaplasia; Methacholine Chloride; Mice; Mice, Inbred BALB C; Mice, Knockout; Natural Killer T-Cells; Occupational Diseases; T-Lymphocytes; Trinitrobenzenesulfonic Acid

We have found a novel anti-allergic agent, M50367, which suppresses IgE biosynthesis and eosinophil accumulation in vivo. In this study, we evaluated the ability of M50367 to modulate Th1/Th2 balance in Th2-background BALB/c mice and to inhibit airway hyperresponsiveness in a murine model of atopic asthma. Oral M50367 at 3-30 mg/kg/day exhibited 51 to 73% reduction of IL-4/IL-5 production and 2- to 5-fold augmentation of IFN-gamma production by Ag-stimulated cultured splenocytes of the mice sensitized with DNP-Ascaris. These alterations in Th1/Th2 cytokine production were accompanied by 55-85% suppression of plasma IgE level. Oral M50367 at a dose of 10 mg/kg/day significantly inhibited Ig-independent peritoneal eosinophilia by 54%, which was induced by repeated i.p. injections of Ascaris suum extract. To develop airway hyperresponsiveness caused by allergic airway inflammation, BALB/c mice were sensitized with i.p. OVA injections, followed three times by OVA inhalation. Oral M50367 significantly inhibited the increase in airway reactivity to acetylcholine, together with the elevation of plasma IgE level and pulmonary eosinophilia, which were observed in vehicle-treated mice 1 day after the last inhalation. Moreover, M50367 treatment reduced IL-4 and IL-5 production and tended to enhance IFN-gamma production, not only by cultured splenocytes, but also in bronchoalveolar lavage fluid. These results suggest that M50367 has a modulating ability of Th1/Th2 balance to down-regulate Th2 response in the circulating system as well as at the sites of inflammation, and may be beneficial for the treatment of allergic disorders such as atopic asthma.

Topics: Adjuvants, Immunologic; Administration, Oral; Animals; Anti-Allergic Agents; Antibody Specificity; Antigens, Helminth; Ascaris suum; Asthma; Benzimidazoles; Bronchial Hyperreactivity; Dinitrobenzenes; Disease Models, Animal; Eosinophilia; Hypersensitivity, Immediate; Immunoglobulin E; Immunoglobulins; Male; Mice; Mice, Inbred BALB C; Peritoneal Lavage; Spleen; Th1 Cells; Th2 Cells

Rabbit antiserum to guinea pig IgE was prepared. This antiserum absorbed IgE antibodies to dinitrophenyl determinants when examined by passive cutaneous anaphylaxis. This antiserum also provoked contraction of tracheal rings from normal guinea pigs in vitro. This system is a new model for asthma in which only IgE among immunoglobulins reacts.

Topics: Animals; Antibodies; Asthma; Chemical Fractionation; Dinitrobenzenes; Disease Models, Animal; Guinea Pigs; Immunodiffusion; Immunoglobulin E; Muscle Contraction; Nippostrongylus; Ovalbumin; Passive Cutaneous Anaphylaxis; Rabbits; Trachea

Topics: Airway Resistance; Animals; Antigens; Asthma; Cattle; Dinitrobenzenes; Dogs; Epitopes; gamma-Globulins; Haptens; Immune Tolerance; Immunoglobulin E; Immunosuppression Therapy; Ovalbumin; Respiratory Hypersensitivity