Uveitis (intraocular inflammatory diseases) is the cause of approximately 10% of severe visual handicap in the United States. Current therapy is based on topical or systemic corticosteroid, with or without second line agents such as cyclosporine A or anti-metabolites. Serious adverse effects of these drugs are the impetus for development of less toxic and more specific therapies for uveitis. Experimental autoimmune uveitis (EAU) is a well-characterized animal model of human uveitis and studies of monkey and rodent EAU have led to identification of the retinal proteins, S-Antigen and IRBP, as putative autoantigen of uveitis. There is significant interest in developing a therapeutic vaccine against uveitis, with particular emphasis on tolerance induction to S-Antigen, IRBP and/or other putative uveitogens (recoverin, opsin). We previously showed that activation of STAT pathways is developmentally regulated and plays a role in dendritic cell (DC) differentiation and maturation. For example, the STAT6 signaling pathway is constitutively activated in precursor DCs (pDCs) and immature DCs (iDCs) but declines as these DCs differentiate into mature DCs (mDCs) and the decline in STAT6 activation correlates with upregulation of SOCS proteins (J Immunol. 172:2307-15). In contrast, STAT1 signaling promotes DC maturation and is most robust in mDCs. However, unlike the STAT6 pathway, STAT1 signalling is not under feedback regulation by SOCS proteins, indicating that STAT1 and STAT6 pathways are distinctly regulated in developing and mature DC. Thus, STAT1 and STAT6 appear to be lineage markers of mDCs and iDCs, respectively. In this fiscal year the thrust of our work has been to exploit the differential utilization of STAT proteins in dendritic cell populations to generate highly purified iDC by specifically deleting STAT1 gene in DC preparations. We have therefore generated several siRNA constructs and are analyzing the efficiency and feasibility of siRNA technology to silence expression of STAT1 or upregulate STAT6 by silencing SOCS genes. Our ultimate goal is to load the purified iDCs with immunopathogenic epitopes of IRBP or S-Antigen for use as therapeutic vaccines against uveitis.
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