Although it is well known that the major cause of allergic diseases is an overproduction of IgE antibodies, the regulation of IgE antibody formation is still poorly understood. Recently, it has been shown in both mice and man that Interleukin-4 (IL-4), a product of T helper cells, induces B cells to secret IgE. Additionally, IL-4 stimulates murine B cells to secrete IgG1 and, as shown recently in our laboratory, human B cells to secrets IgG4. However, the mechanism of human IgE/IgG4 formation in vitro differs from that in the mouse and is presently not fully understood. Human B cells in mononuclear cell preparations but not purified Beta cells incubated with recombinant IL-4 (riL-4) secrets IgE/IgG4, suggesting that a non-B cell population is necessary for human rIL-4 induced IgE secretion. In addition, we found that polyclonal Beta cell activators inhibit the human rIL-4 induced IgE/IgG4 secretion. Another unresolved issue in Il-4 induced IgE formation is the preferential interaction of allergens with IL-4 producing T helper cells. Preliminary experiments in mice suggest that antigen presenting cells may play an important role in causing T helper cells to differentiate into IL-4 secreting cells. The goal of the proposed research is centered on three open questions regarding IL-4 induced IgE secretion: 1) What are the cellular requirements for human rIL-4 induced IgE/IgG4 secretion in vitro? What is the role of antigen-presenting cells in the differentiation of T helper cells to become IL-4 secreting cells? 3) Do human allergen specific T cell clones secrete IL-4 but not IL-2/IFN-gamma? The specific aims are: 1) to study the cellular requirement for human rIL-4 induced IgE/IgG4 secretion in vitro and to characterize the Beta cells responding to rIL-4. 2) To analyze the mechanism of suppression of rIL-4 induced IgE/IgG4 secretion by Beta cell activators. 3) To determine whether dendritic cells obtained from different anatomic locations cause differentiation of PHA-responsive murine T cell clones into either IL-4 or IFN-gamma secreting cells. 4) To quantitate the IL- 4, IL-2 and IFN-gamma production by allergen-specific human T cell clones and to use allergen specific T cell clones to develop a human polyclonal Beta cell activation system by coupling the allergen to purified anti- human IgM.
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