This project proposes to translate our studies defining the alterations in human allergic antibody (IgE) responses and allergic inflammation induced by the model xenobiotic diesel exhaust particulates (DEP) into the arena of interventional studies. We have defined and refined two models of the effect of DEP on human allergic airway disease; (i) enhancement of established allergic/IgE responses and (ii) primary sensitization to a neoallergen, and elucidated the underlying cellular and molecular mechanisms for the DEP adjuvant effect. Using these models, we have shown, both in vivo and in vitro, that DEP and extracts of DEP have direct and indirect immunoregulatory effects on human allergic inflammation and antibody production. Those studies have demonstrated that oxidative stress, early release of IL-4 from basophils/mast cells and a decreased TH-1 like contribution are important elements in the pro- inflammatory pro-allergic adjuvant effects of DEP. Following on from this work, we now propose to test potential therapeutic approaches as """"""""Proof of Principle"""""""" strategies to establish future interventional directions for interrupting-inhibiting the enhanced allergic responsiveness seen with DEP plus allergic exposure. Specifically, we will: (1) Test the hypothesis that anti-oxidants as exemplified by N-acetylcysteine (NAC) will inhibit DEP enhancement of the human primary and secondary allergic response in vivo by blocking the initial DEP induced oxidative stress. Test the hypothesis that topical sIL-4R will inhibit DEP enhancement of the primary secondary human allergic response in vivo by blocking the DEP related early IL-4 release and will modulate the nature of the local immune response and block the DEP enhancement of the primary and secondary human allergic response in vivo by counteracting the Th-2 skewing that results from DEP exposure. In each of these aims, we will determine the outcome in terms of both allergic inflammation and specific antibody IgE production. In addition, in collaboration with Dr. Andre Nel (Project 2) and Dr. Herschman (Project 3), the specific effects of these interventions on key aspects of the mechanisms involved in DEP enhancement of allergic inflammation will also be tested. Key parameters assessed will be i) the level of oxidative stress generated, ii) mast cell/basophil histamine and early IL-4 release, iii) production of sentinel chemokines and cytokines such as RANTES, IL-4 and interferon-gamma, and iv) production of antigen specific IgE antibody. This project will also be involved in collaborate aims with project 2, 3 and 4. We will assist Project 2 & 4 in using our models of primary and secondary allergic responses to test the responses of individuals with functional polymorphisms of key oxidant (phase II enzyme) pathway genes (HO-1, GMST1, NQO-1) and assist Project 3 in testing the effects of cyclooxygenase inhibition in our models of secondary allergic responses.
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