Allergic rhinitis is an airways disease where inflammation plays a central role in its pathogenesis. The studies described in this proposal are designed to improve our understanding of the mechanisms by which cytokines amplify or modulate the initial inflammatory response to an inhaled antigen. New information has deeply implicated inflammatory processes in the etiology of airway allergic disorders; proinflammatory cytokines are now recognized to contribute to these immunologic events. Experiments described in this proposal will further assess the role(s) of cytokines in mechanism of allergic reaction and test the hypothesis that IL-1 plays a principal role in the regulation of early events in allergic inflammation. the PI will examine the biochemical and cellular mechanisms of inflammation caused by nasal antigen challenges and ongoing natural allergen exposures. Inflammation will be assessed by examination of cells and mediators in nasal washings and by measurement of cytokines in nasal secretions using a matrix method. Initial studies have demonstrated the recovery of IL-1, -5, -6 and GM-CSF in nasal mucosal secretions following antigen provocations. In addition, cytokine- secreting cells will be identified and enumerated by utilizing in situ hybridization for mRNA expression, immunocytochemical staining for cytoplasmic cytokines, and enzyme-linked immunospot assay for cytokine secretion of individual cells. A potential mechanism for interference with IL-1 activity, involving an IL-1 receptor antagonist protein (IRAP), has been described. To determine whether IRAP inhibits cytokine synthesis, in vitro methods will be utilized. Moreover, IgE production will also be analyzed from these culture experiments. Preliminary results have shown that IRAP inhibited antigen-induced synthesis of TNF, GM-CSF, and IgE antibody in a dose-dependent manner. Aside from IL-1, the other focus of this research is on those TH2 cytokines which have proallergic activities (e.g., IL-3 to -6, and GM-CSF). It is anticipated that the studies described above will further our knowledge of the mechanism of cytokine-mediated inflammatory events during allergic reactions. Inhibition of IL-1 bioactivity, including modulation of subsequent production of other cytokines and IgE, by IRAP suggests the potential benefits of using this inhibitor in future therapies for atopic diseases.
| Sim, T C; Reece, L M; Hilsmeier, K A et al. (1995) Secretion of chemokines and other cytokines in allergen-induced nasal responses: inhibition by topical steroid treatment. Am J Respir Crit Care Med 152:927-33 |
| Sim, T C; Hilsmeier, K A; Reece, L M et al. (1994) Interleukin-1 receptor antagonist protein inhibits the synthesis of IgE and proinflammatory cytokines by allergen-stimulated mononuclear cells. Am J Respir Cell Mol Biol 11:473-9 |
