Asthma is an inflammatory disorder of the airways manifested by reversible airflow obstruction and bronchial hyperreactivity. Tumor necrosis factor-a (TNF-a) is a primary pro-inflammatory cytokine with pleiotriopic biological functions which may play an important role in the pathogenesis of 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. To assess the future utility of anti-TNF therapy in asthma, 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. Concurrent laboratory studies are focused on identifying mechanisms via which TNF bioactivity is regulated by airway epithelial cells. Shedding of cell surface TNF receptors can attenuate TNF bioactivity via the generation of soluble TNF binding proteins and by decreasing the number of cell surface TNF receptors available for ligand binding. The mechanism underlying shedding of the soluble type I, p55 TNF receptor (TNFR1) is unknown, but prior work has suggested that TNFR1 shedding may involve proteolytic cleavage via an unknown metalloprotease. Utilizing a yeast two-hybrid approach, our laboratory has identified a zinc metalloprotease which is expressed by human airway epithelial cells and may be involved in the processing of TNFR1 to a soluble form. We are currently characterizing the function and expression of this novel enzyme. - Asthma, Airway Inflammation, Tumor Necrosis Factor, Soluble Tumor Necrosis Factor Receptor - Human Subjects
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