Asthma is a chronic inflammatory process mediated by aberrant adaptive (antigen dependent) and innate immune responses. Epidemiological studies have shown a correlation between exposure to endotoxin (LPS) during the first year of life and a lower prevalence of asthma. Experimental evidence supporting the notion that LPS responses affect asthma comes from our Preliminary Studies, which demonstrate that the LPS receptor TLR4 (Toll-like-receptor 4) regulates allergic responses in an established murine model of allergic asthma. Mice deficient in the key-adapter protein MyD88, critical for TLR4 signal transduction, have dramatically increased allergic responses. The data support our major postulate that the TLR4/MyD88 pathway plays a key-role in the suppression of allergic responses. Further support for this hypothesis comes from our observations that NF-kappaB which is activated by the TLR4/MyD88 signaling pathway, is crucial for pulmonary allergic inflammation. Our goal is to determine the mechanisms involved in TLR-4 mediated suppression of allergic responses. The fundamental strategy is to examine the contribution of the key molcules, TLR4, MyD88 and NF-kappaB in the modulation of allergic immune reponses.
In Aims 1 and 2 we will examine how TLR4 signaling in T lymphocyte subsets and dendritic cells is critical for the pathogenesis of asthma. In our analysis of T cells, we will also determine whether CD4+CD25 + T regulatory (T regs) cells are critical regulators of allergic responses.
In Aim 3, we propose to investigate the role of NF-kappaB genes in the modulation of allergic responses. The studies are designed to test our overall hypothesis that engagement of TLR-4 under defined conditions decreases allergic responses. Together, these experiments propose to clarify the interplay between innate and adaptive immunity in the development of pulmonary allergic inflammation, which may suggest therapeutic strategies applicable to allergy or asthma.
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