Over the past two decades information regarding the eosinophilic leukocyte has dramatically increased. It is now appreciated that the eosinophil has the ability to kill parasites in vitro and likely does so in vivo and that eosinophils most probably serve as effector cells for damage to tissues in hypersensitivity diseases. Prior studies supported by this grant resulted in the isolation of the major eosinophil granule proteins, production of antibodies to these proteins and development of methods to investigate the role of the eosinophil in disease. Because eosinophil granule proteins are potent toxins in vitro, their deposition onto tissues in association with. damage to these tissues is a strong argument for an effector role of the eosinophil and its toxic granule proteins in disease. Furthermore, in certain diseases, such as atopic dermatitis, degranulation can occur without a marked increase in the number of eosinophils in tissues. Eosinophilia is now recognized as being under the control of cytokines, specifically interleukin (IL)-3, IL-5 and the granulocyte/macrophage-colony stimulating factor (GM-CSF). Thus, one can argue that the proper characterization of an eosinophil associated disease involves not only the identification of eosinophil degranulation and deposition of toxic proteins onto damaged tissues, but also elucidation of the mechanism of the eosinophilia. This grant application focuses on the elucidation of the mechanisms of eosinophilia and eosinophilia associated diseases. Four goals are identified. First, the cytokines present in body fluids of individuals with eosinophilia will be identified and quantitated using an exquisitely sensitive assay for eosinophil activating cytokines, namely the eosinophil survival assay. Second, cells producing cytokines will be investigated with particular attention to T cells and mast cells by in situ hybridization and immunofluorescence for the cellular localization of GM-CSF, IL-3 and IL-5. Third, T cell clones will be established from patients with eosinophilia to test the hypothesis that clones producing eosinophil active cytokines are disproportionately increased in number in the blood of patients with eosinophilia. Fourth and finally, patients with eosinophilia will continue to be monitored in order to determine whether or not novel syndromes can be identified. Note that this grant served as the """"""""nidus"""""""" of investigations which resulted in the identification of the eosinophilia-myalgia syndrome, an epidemic of disease which ultimately has been traced to the ingestion of contaminated batches of L-tryptophan. Thus, this grant supports investigations to further our understanding of the pathophysiology of eosinophil associated disease, and it also monitors these diseases in clinical practice.
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