REGULATION OF EOSINOPHIL SURVIVAL

University Of Chicago, Chicago IL

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Abstract

Asthma is a serious disease that can have debilitating and sometimes fatal effects on its sufferers. One of the hallmarks of the lung inflammation that occurs in asthma is the marked increase of eosinophils in the tissue as well as the airways. Since eosinophils are one of the major cell types involved in the pathology of asthma, the clearance of airway eosinophilia is an important step in the resolution of airway inflammation. Preliminary results have found that Fas (CD95), a cell surface receptor that when ligated can induce cell death via apoptosis, is an important mechanism of airway eosinophilia resolution. Although Fas and its ligand FasL were first defined as receptors on T lymphocytes, recently have bout been found to be expressed by various cells in the body. In the lungs, the Fas receptor has been found expressed on airway epithelium, smooth muscle, and inflammatory cells such as T cells, eosinophils, and neutrophils, while FasL expression is limited to T cells, monocytes, and airway epithelium. When murine BAL cells from mice with experimentally induce airway inflammation are cultured the eosinophils die rapidly via a Fas-dependent mechanism. This cell death can be countered, in part, by the addition of exogenous cytokines such as IL-5. In addition, in a murine model of allergic airway inflammation, we have recently found that mice that are deficient for the Fas receptor fail to resolve airway eosinophilia as fast as wild type controls. These data suggest that our results in vitro reflect in vivo mechanisms of airway inflammation resolution. Thus, the survival of eosinophils may be regulated by a balance between soluble factors that enhance survival and cell:cell interactions that lead to Fas- mediated cell death. The central hypothesis of this proposal is that T cells, which are major producers of these cytokines and express FasL upon activation, play a key role in the regulation of eosinophil survival. Therefore, the overall goal of this proposal will be to dissect the role of T cells in the regulation of airway eosinophilia through both in vitro and in vivo experimental systems. To address these goals the following studies are proposed. (1) It will be determined whether Fas-mediated cell death is a major mechanism involved in the resolution of airway inflammation. (2) The role of T cells the Fas-induced apoptosis in vitro and in vivo will be determined. (3) The role of different T cell subsets and T cell cytokines the survival of death of eosinophils will be determined.