Our current efforts in this area are two-fold. First, we continue to study the role of cyclic nucleotide phosphodiesterases in the regulation of antigen-driven T cell responses.
Our specific aims are: 1. To define the potential of PDE4 inhibitors to mediate the induction of antigen-specific T cell tolerance, using the ovalbumin-sensitized balb/c mouse model. 2. To define the potential of PDE4 inhibitors to mediate synergistic immunosuppression in vitro when studied in combination with various immunosuppressive agents. 3. To define the potential of PDE3, PDE4, and PDE7 inhibitors to mediate beneficial effects on collagen homeostasis. 4. To define the potential of PDE7 inhibitors, alone or in combination with PDE3 and PDE4 inhibitors, to mediate antigen-specific immunomodulatory activity in human T cells. Second, we have recently identified an open reading frame on chromosome 6p12 with 3 exons and a predicted length of 153 amino acids. The 3' half of this gene demonstrates 73% DNA sequence homology and 60% amino acid sequence homology with human interleukin-17; the 5' half of this gene demonstrates no significant sequence homologies. RT-PCR demonstrates upregulation of expression upon antigen stimulation of Th0, Th1, and Th2 clones, with constitutive expression limited to Th1 clones. RT-PCR also detects expression in resting and activated basophils, as well as bronchoalveolar lavage samples following allergen challenge of allergic asthmatic subjects. Tissue distribution studies suggest expression limited to T cell hematopoietic regions. We have designated this gene """"""""IL-X"""""""" and have recently expressed it as a 6-His tagged product.
Our specific aims for this project are: 1. To more fully characterize the tissue expression pattern for IL-X in normal and disease states. 2. To generate reagents for detection and quantitation of IL-X. 3. To initiate both functional and pharmacologic studies of IL-X in order to determine the potential immunoregulatory significance of this new cytokine.
