The research proposed in this competing renewal application will build on important information gained from studies of the regulation of human IgE synthesis during the first three years of support under the current grant. This work has been made possible by the discovery of optimal conditions for inducing human IgE synthesis in vitro. The work will focus on T cells and the cytokines they produce and has the following specific aims: 1) to define the cytokine profiles and CD23 expression of T cell clones derived from high and low IgE producing humans after in vitro activation with different stimuli selected for their known effects on non-cloned T cells; 2) to extend studies of the expression of CD45 isoforms and of the beta1 integrin, CD29, on T cells from high and low IgE producers as a possible means of identifying differences in T cell subpopulations relevant to IgE dysregulation and to signals provided by T cells to B cells responding to recombinant human interleukin 4 (rhIL-4); 3) to examine T cells from different human disease states characterized by excessive IgE production (e.g. Hyper IgE Syndrome, Wiskott-Aldrich syndrome, atopic dermatitis, and other atopic states) for common or different T cell characteristics; 4) To determine the effects of Staphylococcus aureus cell wall products (teichoic acid, peptidoglycan) and enterotoxin B on rhIL-4-induced B cell IgE synthesis and CD23, CD45 isoform and CD29 expression and cytokine profiles of T cells from humans with and without excessive IgE production; 5) to investigate the various signals enabling B cells to respond to rhIL-4 and to those augmenting that response; 6) to determine whether Ti gamma/delta antigen receptor-bearing T cell clones provide a more effective second signal than Ti alpha/beta-bearing clones for B cell rhIL-4-induced IgE synthesis; and 7) to extend studies of the effects of other cytokines, naturally occurring biologic molecules and pharmaceutical agents on rhIL-4-induced human IgE synthesis.
