The IgE antibody system plays an important role in the pathogenesis of human allergic diseases. A detailed understanding of the mechanisms regulating the human IgE response is essential for the development of new therapeutic strategies in the treatment of allergic diseases. We propose to study the cellular and molecular events involved in the induction and regulation of IgE synthesis in man. For these experiments we have available a battery of reagents which are necessary for studies of human IgE regulation. These reagents include alloreactive and antigen specific helper T cell clones which induce IgE synthesis in B cells from both normal and allergic subjects, human T-T hybridomas which secrete IgE binding factors that modulate IgE synthesis, a cDNA probe for the human IgE gene, bacterial products of the cloned human IgE gene and its fragments, monoclonal antibodies to the Fc portion of human IgE, anti-idiotypic antisera to human anti-ragweed antibodies, and ragweed antigen E conjugated to human IgG. The experiments proposed will focus on: 1) the mechanisms of induction of IgE synthesis by cloned helper T cells. Specifically we will examine the surface isotype and physical characteristics of the responding B cells, determine if direct T-B cell interaction is required, assess the role of alloreactive T cells in the induction of IgE synthesis during acute graft vs. host disease; 2) the effect of T cells and T cell subsets from normals and allergic subjects on the induction of IgE synthesis by T cell clones; 3) the regulation of IgE synthesis by IgE binding factors (IgE b.f.) derived from T-T hybridomas and human sera. Specifically we will study the role of glycosylation on the biologic activity of the IgE b.f., the site recognized by the IgE b.f. on the IgE molecule and the effect of IgE b.f. on the level of IgE mRNA in IgE secreting B cell lines; 4) the effect of antigen, antigen IgG conjugates and anti-idiotypic antibodies on ragweed antigen E specific antibody synthesis. Monoclonal antibodies to IgE b.f. will be raised to facilitate the study of these factors and a search will be initiated for autoantiidiotypic antibodies in patients receiving immunotherapy. The results of these proposed studies could have long term relevance in the future attempts to selectively inhibit the human IgE response while leaving the IgG response intact. Such discoveries could be applicable in future designs of treatments for allergic diseases. The basic significance of this work in general is to define the mechanisms of isotype and antigen specific control IgE synthesis in man.
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