Interferon-gamma (IFN-gamma), a promising agent for the treatment of IPF, is also the most potent known stimulant of host defense against bacterial, fungal and viral infections. We hypothesize that unlike the immunosuppressive drugs prednisone and azathiopnine, IFN-gamma reduces the infectious pulmonary complications of IPF and their adverse effects on the clinical course and respiratory performance. We propose to compare the effects of immunosuppressive regimens vs. IFN-gamma on innate mucosal host defenses and to identify specific mechanisms and molecular effectors that are modulated by the contrasting treatment modalities. We will: 1. Compare the effects of IFN-gamma vs. high dose prednisone on the composition and density of nasal and pharyngeal microbial flora. 2. Analyze the effects of IFN-gamma vs. high dose prednisone on known effector proteins of innate host defense in nasal epithelia 3. Analyze the effects of IFN-gamma vs. high dose prednisone on known effector proteins of innate host defense in the lower airways 4. Using proteomics, identify novel proteins (potential effectors and mediators) whose concentrations in nasal or lung fluids are induced or suppressed during treatment with IFN-gamma vs. high dose prednisone As a subsidiary objective, we will sample the azathiopnine-treated patients to test the hypothesis that like high dose prednisone, azathioprine will also have suppressive effects on mucosal host defense compared to IFN-gamma In the aggregate, this study will explore novel concepts of the modulation of mucosal host defenses by immunostimulatory vs. immunosuppressive agents. This is an exciting opportunity to study these mechanisms under well-controlled conditions in humans. The proposal also explores a novel alternative mechanism for the potentially beneficial effect of IFN-gamma in IPF-the avoidance or active prevention of secondary infections that exacerbate the clinical course of conventionally-treated patients with this disease.
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