The goal of this project is to better characterize the role of tumor necrosis factor (TNF) in the pathogenesis and treatment of asthma. TNF is capable of up-regulating a variety of important pro-inflammatory gene products that may contribute to asthmatic airway inflammation. Although anti-TNF approaches have been effective in animal models of asthma, the efficacy of an anti-TNF strategy in humans has not been studied. We have initiated a Phase II clinical trial utilizing a soluble, dimeric fusion protein comprised of the extracellular ligand-binding domain of the human p75 TNF receptor linked to the Fc portion of human IgG1 (TNFR:Fc). TNFR:Fc functions by binding TNF and blocking its interaction with cell surface receptors. This randomized, double-blinded, placebo-controlled, proof of concept trial will utilize a bronchoscopic segmental allergen challenge model in mild atopic asthmatics not requiring corticosteroid therapy. Four doses of TNFR:Fc will be administered via subcutaneous injection over a two-week period. Soluble and cellular inflammatory markers, as well as physiological parameters will be assessed pre- and post-TNFR:Fc therapy and following bronchoscopic segmental allergen challenge. The data generated by this study will assess the utility of future trials of anti-TNF therapy in asthma. Laboratory investigations are also being conducted to identify the mechanism via which ectodomain shedding of cell surface TNF receptors is regulated. For example, shedding of TNF receptors may have an anti-inflammatory effect via the generation of soluble TNF binding proteins and by decreasing the number of cell surface TNF receptors available for ligand binding. Prior work has suggested that TNFR1 shedding may involve proteolytic cleavage via a zinc metalloprotease. Our laboratory has identified a zinc metalloprotease that is expressed by airway epithelial cells and may participate in the regulation of TNFR1 ectodomain shedding. Ongoing investigations are assessing the function and expression of this novel enzyme.
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