Regulation of asthma by Btk and family kinases

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DESCRIPTION (provided by applicant): The incidence of allergic diseases, particularly asthma, has been increasing at the troubling pace of doubling during the last two decades in developed countries. Given the limited success in preventing and treating asthma and sometimes serious side effects of the current regimen with corticosteroids, it is obvious that we need to broaden our therapeutic choices for this and other allergic diseases. We and others have demonstrated the critical importance of Bruton's tyrosine kinase (Btk) in the activation of B and mast cells, two cell types that are involved in the pathophysiology of these diseases. When airway inflammation experiments, a disease model of asthma, were performed with btk -/- mice, we were surprised to find that btk -/- mice exhibited exaggerated inflammatory and immune responses. Immunization of these mice with ovalbumin induced an enhancement in production of not only type 2 helper T cell (Th2)-dependent IgE and IgG1 antibodies but also type 1 helper T cell (Th1)-associated IgG2a antibodies. These results suggest that mice lacking functional Btk tend to develop exaggerated immune responses characterized by both Th1 and Th2 cells upon exposure to inhaled allergen. Numerous studies point to the central role of dendritic cells (DCs) in orchestrating the Th development and activation. Our preliminary results demonstrated that Btk is expressed in bone marrow derived DCs (BMDCs) and splenic DCs and that BMDCs derived from btk -/- mice exhibit increased upregulation of MHC class II molecules in response to lipopolysaccharides, compared to wild-type cells. Our data also indicate that splenic DCs from btk -/- mice have a stronger ability to stimulate antigen-specific T cell proliferation and production of both Th1 and Th2 cytokines. These results prompt us to investigate roles of Btk in the development, maturation and function of DCs in the context of Th2-dependent airway inflammation as well as in non-Th2-dependent situations. Since BMDCs express Tec, a close relative of Btk, and several Src family kinases, that can regulate Btk activity, it will also be important to study roles of these kinases in DC biology. This is a poorly explored area in DC biology. Our efforts will hopefully identify novel targets for pharmaceutical intervention to treat asthma and other immune diseases.