This grant proposes to study the role of the lymphokine, Lymphocyte Chemoattractant Factor (LCF), in asthmatic inflammation. LCF is preformed and selectively secreted from CD8+ T cells within four hours following histamine stimulation via H2 receptors, in addition to its synthesis and release following activation by mitogens and antigen. It is a potent chemoattractant and activator of CD4+ T lymphocytes, monocytes, and eosinophils. Of particular importance is its ability to drive resting T cells into the cell cycle associated with expression of IL2R and synthesis and secretion of GM-CSF. It is our hypothesis that mast cell secretion of histamine following allergen activation results in LCF secretion from airway (T)cells. The rapid appearance of LCF initiates the earliest chemoattraction of CD4+ T cells, monocytes and eosinophils which are subsequently activated to release their own cytokines.
Our first aim will identify the time course for the appearance of LCF following antigen and histamine challenge, compare this with the time course of generation of other asthma related cytokines and determine the cell of origin of LCF in the airways. In our second aim we propose to determine the role of LCF in the amplification of the inflammatory response by delineating the mechanism of histamine-induced LCF release, and LCF's effects on CD4+ T cell and monocyte cytokine synthesis. As regards the first aim, we have confirmed the presence of LCF in BAL and airway mucosa of antigen and histamine challenged asthmatics 4-6 hrs following challenge when there are no detectable levels of TH2 cytokines. By 24 hours a number of cytokines are present including IL-3 and 5 while LCF levels persist. In order to support the importance of our second aim we have demonstrated LCF in the supernatants of histamine stimulated blood CD8+ T cells and CD8+ T cell clones derived from the airways of asthmatic individuals and shown that LCF induces CD4+T cell GM-CSF mRNA, protein synthesis and secretion. We believe that these preliminary data strongly suggest a possible direct role for LCF in the initiation of the early inflammatory response in allergen induced asthma by chemoattraction of CD4+ cells and an indirect role in the perpetuation of the chronic inflammatory response by activation of CD4+ cells to secrete other cytokines.
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