Asthma is considered to be a chronic inflammatory disease and the airways hyperresponsivess (AHR) and bronchospasm that are characteristic of asthma are believed to be the result of this inflammatory process. The airway inflammatory infiltrate consists of a variety of cell types, including lymphocytes and eosinophils. Activated CD4T lymphocytes have been identified in bronchial biopsies and lung lavage fluid from asthmatics and they have been shown to express mRNA for the cytokines Il-4 and IL-5. High serum levels of IgE and eosinophil accumulation in the bronchial mucosa are characteristic of asthma and these features are dependent on the secretion of IL-4 and IL-5. Thus, the Th2 cell appears to play a critical role in the pathogenesis of the asthmatic diathesis. Definite documentation of the role that these cells play, however, is lacking. In addition, the processes that regulate CD4 T cell differentiation into Th1 or Th2 in the lung have not been investigated. CD4 T cells are stimulated by antigens to differentiate into Th1 or Th2 cells which differ in their effector functions and the profile of cytokines they produce when activated. Several different factors have been shown to influence this process. Studies from our laboratory have demonstrated that properties of the antigen itself play an important role in the regulation of naive CD4 T cell differentiation. In addition, other laboratories have shown that altering the cytokine microenvironment during T cell activation influences whether Th1 or TH2 cells will be induced. These processes have not been investigated in the respiratory system. In this proposal we plan to 1) Characterize the role of antigen in the stimulation of Th1 or Th2 responses in the lung. 2) Characterize the role of the cytokine microenvironment int he generation of Th1 or Th2 lymphocytes in the lung. 3) Define the relationship between induction of Th2 cells and the development of AHR and inflammation. These studies will expand our understanding of CD4 T cell responses in the lung by defining factors which influence the development of Th1 and Th2 cells. The models of CD4 T cell subset induction that are proposed include unique transgenic systems in which to study the role of Th2 cells in the development of AHR and bronchial inflammation.
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