Mycobacterial Antigens and Immunomodulation in Allergic Asthma
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Authors
Hopfenspirger, Michael Todd
Issue Date
2003-02
Volume
Issue
Type
Dissertation
Language
en_US
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Alternative Title
Abstract
The disease asthma is characterized by the hallmark features of airway hyperresponsiveness (AHR), increased serum concentrations of IgE and type 2 cytokines, and tissue and bronchoalveolar lavage (BAL) eosinophilia. It has seen an increased prevalence in recent decades. Such a rapid increase suggests a significant role for environmental factors. A candidate among these environmental factors is, paradoxically, the decreased prevelance of infectious diseases in westernized nations, a decrease achieved by vigorous vaccination programs. Several investigators have observed an inverse correlation between atopic diseases, such as asthma, and exposure to intracellular pathogens, namely mycobacteria. In attempts to further link these two phenomena, investigators have begun administering immune modulators, including BCG, an attenuated strain of M. bovis, to mice in antigen (ovalbumin, Ova)-induced asthma models. Data in these models have been mixed, with conflicting IgE responses and scant information on the effects on pulmonary functions. Another type 1 cytokine-inducing immune modulator, Flt3-ligand (FL) has yet to be tested for its theoretical potential for attenuating asthma in an animal model. Therefore, I designed a series of experiments to more completely characterize the role of the immune modulators, BCG, Mycobacterium vaccae and FL, in a mouse model of asthma. Mycobacteria were administered to mice either prior to or following sensitization with Ova. while FL was administered prior to Ova sensitization. These protocols were followed by comprehensive assessment of the hallmark features of asthma, which included assessment of pulmonary function, measurement of BAL eosinophilia, serum total and antigen-specific IgE antibodies and serum and BAL cytokines. While M. vaccae was partially successful in attenuating these features, BCG was consistently shown to attenuate the LAR, AHR and BAL eosinophilia. FL was also able to attenuate these outcomes. None of the treatments had any effect on the EAR. Furthermore, BCG was able to maintain suppression of the LAR (with suppression of the EAR) together with the suppression of the growth factor TGF-[3 and the chemokine eotaxin in a mouse model of chronic asthma. However, BCG was ineffective in preventing airway remodeling, as measured by thickness of airway and tracheal collagen and airway epithelium. These results suggest that BCG and FL are potential candidates for clinical application as immune modulators in suppressing or preventing allergic asthma.
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Publisher
Creighton University
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