The long-term objective of this research proposal is to understand the role of interleukin 4 (IL-4) in the development of the T lymphocyte lineage and in the regulation of certain immune and inflammatory responses. The approach chosen is a genetic one; that is, to study both dominantly-acting and null mutations of the IL-4 gene in vivo in mice and thereby analyze the consequences of IL-4 overexpression and deficiency, respectively. IL-4 dominant and null mutation mice will be used to study the actions of IL-4 in lymphoid development in experiments involving surface phenotype analysis of immature and mature lymphocyte populations, adoptive transfer studies of bone marrow and thymocytes, analysis of thymic epithelial populations, and expression and functional analyses of thymic adhesion molecules. These studies will provide a physiologic assessment of a postulated role for IL-4 in the intrathymic development of T lymphocyte precursors. In addition to studies of thymocyte development, IL-4 mutant mice will also be used to studied the role of IL-4 in the initiation and maintenance of inflammatory responses characterized by mast cell hyperplasia and eosinophil infiltration. Using sensitive RNA and protein assays, a determination of other cytokines coordinately expressed by T cells, and non-lymphoid cells, at the site of these lesions will also be made, as an initial step in defining the cytokines required for the development of the inflammatory pattern. The role of IL-4-induced changes in endothelial adhesion molecule expression and inflammatory cell homing will also be studied. The association of IL-4 and this characteristic inflammatory response with helminthic parasite infections, human allergy, and a broad-spectrum antitumor activity suggests that a better understanding of IL-4 function in vivo may provide innovative approaches for the treatment of certain human disorders.
