The focus of this ongoing study is to define the relationship between pulmonary IL-5 expression, CD4+ T cell activities, and eosinophil effector functions. Our preliminary studies using transgenic mice demonstrated that IL- 5 and/or eosinophils have previously unrecognized activities which effect CD4+ T cell proliferation, activation, and/or Th2 differentiation. In this renewal, we propose to exploit these observations to test the hypothesis that IL-5 expression and/or eosinophil accumulation in the lung lead to T cell proliferation and activation. The activation of these lung T cells, in turn, elicits/regulates eosinophil effector functions that contribute to allergic pulmonary pathology. In the short term, the proposal seeks to accomplish three specific aims: (i) To define IL-5 and/or eosinophil mediated effects on CD4+ T cells and in particular, to determine the basis of the T cell proliferation in the lungs of IL-5 transgenic mice. Moreover, to ask: are these T cells activated and is this proliferation/activation a direct consequence of IL-5 or an indirect result of IL-5 mediated eosinophil accumulation in the lung?; (ii) To determine whether T cell-mediated activation of eosinophils is an underlying mechanism contributing to allergic respiratory inflammation. Our successful use of eosinophil adoptive transfer will be exploited to determine specific eosinophil-T cell signaling pathways leading to pulmonary pathology; (iii) To determine if a causative relationship exists between eosinophil recruitment and the development of airway pathologies. Specifically, using an eosinophil ablation strategy that we have developed, we will determine whether the pulmonary pathologies occurring in IL-5 transgenic mice, or the pathologies arising in ovalbumin sensitized/aerosol challenged wild type and gene knockout mice deficient of specific immune pathways are dependent on eosinophils. The transgenic and gone knockout approaches described in this proposal will help achieve these goals. Our long-term objective is to determine the causes of asthma and its associated morbidity that more effective strategies for diagnosis, prevention, and therapy might be developed.
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