Allergic diseases affect 20 percent of the population and are characterized by predominance of allergen specific Th2 helper cells and IgE antibody. The cytokine IL-4 plays a critical role in the development of Th2 helper cells and synergizes with CD40 ligand (CD40L) to induce IgE isotype switching. In this proposal, three investigators with long standing interest in the molecular mechanisms of allergic diseases join together again to renew their AADCRC, based at Children s Hospital, with the aim of elucidating the mechanisms of regulation of three key elements in the elements in the development of allergic diseases, namely IL- 4, CD40L and class switch recombination (CSR). In the first project based on her previous findings that the transcription factor c-maf and NFAT regulate IL-4 gene expression, L. Glimcher, proposes to examine the nature of acute and chronic allergic airway disease in c-maf and NFAT genetic mutant mice and to establish whether conditional ablation of c- maf in vivo alter the production of Th2 cytokines and allergic airway disease. She will identify what genes, in addition to cytokines, are regulated by NFAT1 and NFAT4 and search for c-maf interacting proteins that are important for IL-4 production. These studies have direct and important implications for potential interventions aimed at treating allergic disease by inhibiting IL-4 gene expression and generation of Th2 cells. In the second Project based on his observations that glucocorticoids (GC) induce CD40L expression and IgE isotype switching, R. Geha will investigate the cellular targets of GC induction of CD40L expression and GC-mediated CD40L dependent activation of CD40+ cells, will examine the role of the glucocorticoid receptor (GR) and of Glucocorticoid Response Elements (GRE) in the induction of CD40L expression by GC and will analyze functional and physical interactions between GR and NFAT in the CD40L promoter. These studies have important clinical implications because GC are commonly used to treat allergic diseases. In the third Project, F. Alt plans to continue his studies on the molecular basis of CSR. He will delete the HS3b, HS4 elements and various combinations of the 4HS sites of the 3' IgH locus and assay the effects of each mutation on germline transcription and CSR. He will test the hypothsis that negative effects of the inserted p8k-neor cassette are mediated by its transcriptional promoter and will examine whether the 3' IgH regulatory region can compensate for functions of the intronic Emu enhancer element. He will also attempt to elucidate the role of transcription in CSR. The results of these studies have important implications for IgE isotype switching in allergic individuals. The fact that the three projects are inter-related at the intellectual, scientific and technologic levels and that the investigators have established long term collaborations among themselves will improve the cost benefit ratio and result in substantial savings in expenditure of time and money.
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