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Since the beginning of this century, allergen immunotherapy has been widely used to treat allergic disorders. In addition to the long-term clinical efficacy of this therapy, there are immediate beneficial effects as observed in rush immunotherapy for which there is no clear mechanism. We investigated the direct impact of an Ag on its specific IgE in terms of IgE measurability in immunoassays and subsequent binding of IgE to the high-affinity receptor for IgE. As a model we used a chimeric IgE specific for NIP that exhibits similar biologic properties as serum or myeloma IgE. To mimic particulate and soluble allergens we coupled 15 NIP molecules to BSA. Using this "artificial allergen" we could show that the presence of the Ag reduced the IgE measurability in immune assays. Furthermore, IgE binding to the Fc epsilon RI was 60% inhibited in the presence of the Ag shown with an optical biosensor that monitors molecular interactions. In normal basophils passively sensitized with IgE that was preincubated with the Ag, no sulfidoleukotriene release could be induced. Rush immunotherapy may invoke a similar phenomenon, resulting in the short-term alteration of symptoms by blocking or substantially reducing binding of IgE to its high-affinity receptor. Thus, our result may explain some of the short-term beneficial effects observed in rush immunotherapy.

The cellular, molecular, and genetic mechanisms underlying the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD) are not well understood. The purpose of this thesis was to address the hypothesis that microbial infection is important for the development and/or progression of COPD through investigation of how cigarette smoke alters the response to a bacterial challenge in a mouse model of cigarette smoke-exposure. To this end, in chapter 2 of this thesis we tested the hypothesis that cigarette smoke-exposure attenuates the ability of alveolar macrophages to sense microbial antigens through innate pattern recognition receptors. The central point of this study was the observation that alveolar macrophages isolated from cigarette smoke-exposed mice had attenuated expression of typical inflammatory cytokines following microbial stimulation. Building on this main observation, in chapter 3 we questioned what the consequences of this would be to an in vivo bacterial challenge with nontypeable Haemophilus influenzae. We demonstrated that cigarette smoke-exposure resulted in chronic inflammation, this inflammation was exacerbated following bacterial challenge, and perhaps most importantly, the nature of the inflammatory response was altered. Interestingly, an observation from the study in chapter 3 indicated that exacerbated inflammation in cigarette smoke-exposed mice may be beneficial for clearance of the bacteria, but may come at the expense of damage to the lungs. Consequently, in chapter 4 we questioned the strain and dose/ frequency stringencies of cigarette smoke-exposure on the observation of accelerated bacterial clearance. We demonstrated a role for antibodies in bacterial clearance. Collectively, this thesis provides insight into our understanding of COPD by demonstrating that cigarette smoke-exposure alters the pulmonary immune/ inflammatory response to a microbial challenge, which has a detrimental impact on the lungs. Thesis Doctor of Philosophy (PhD)