Autoimmune arthritides, including rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA) are leading causes of long-term disability in the United States. The autoimmune basis of these diseases is well established, but the causes are unknown. Present therapies, while partially effective at controlling symptoms, have shown minimal efficacy at controlling disease progression. This project will test the hypothesis that local expression, by gene transfer, of a naturally occurring inhibitor of Th1-type responses (soluble TNFR; sTNFR) and cytokines which induce immune deviation from a predominantly Th1-type to a Th2-type response (IL-4 and IL-10) can control autoimmune arthritis. The studies will utilize the murine collagen-induced arthritis (CIA) model, which has features of RA. There are three specific aims. First, murine IL-4, murine IL-10, sTNFR, and viral IL-10 (an EBV protein sharing strong sequence homology with murine IL-10) will be studied as candidates for gene transfer to the synovium. Baseline secretion of the pro-inflammatory cytokines IL-2, IFN-gamma, IL-1, TNF-alpha, and IL-6 from synovium of normal and arthritic mice will be determined. The capacity of murine IL-4 and IL-10, viral IL-10, and sTNFR to inhibit secretion of pro-inflammatory cytokines from CIA synovium will be determined. Second, conditions for gene transfer to the mouse synovium will be optimized, using adenoviral gene transfer vectors. The mitotic rate of CIA synovium will be measured. The synovial cells (types A and B) able to be transduced will be determined, as well as the efficiency of transduction of each of these cell types. Potential immune responses directed against the vectors and their transgene products will be analyzed and correlated with duration of transgene expression. Third, the effects of gene transfer of murine IL-4 and IL-10, viral IL-10, and sTNFR on CIA will be determined. Effects on disease severity will be measured, with analysis of quantity and quality of synovial inflammation. The effects on T and B cell autoimmune responses to type II collagen are expected to be determined. The long-term goal is to utilize the knowledge gained from these studies to develop approaches for the clinical use of gene transfer as a therapy for autoimmune arthritis.
