Abstract
TNF-alpha antagonists such as anti-TNF-alpha monoclonal antibodies or soluble tumor necrosis factor receptors have proven to be useful therapeutics for the treatment of autoimmune inflammatory diseases including rheumatoid and psoriatic arthritis. Recently, we have demonstrated that local (intra-articular) or systemic (intramuscular) administration of an AAV2-ratTNFR:Fc vector, encoding the rat tumor necrosis factor-a receptor: immunoglobulin (IgG1) Fc fusion gene, to rats with experimental arthritis led to suppression of disease as reflected in decreased inflammatory cell infiltration, pannus formation, cartilage and bone destruction, and mRNA expression of joint proinflammatory cytokines. In the current study we employed a monoarticular arthritis model in rats that allow us to evaluate the long-term effect of TNFR:Fc expression on recurrence of joint inflammation. Monoarticular arthritis was initiated by injection of a small dose of peptidoglycan-polysaccharide polymers (PG-APS) isolated from cell walls of group A streptocci into the hind ankle joints. This resulted in a flare of inflammation that resolved within 5 to 7 days. Thirty-two days later, reactivation of joint inflammation was induced only in the joints previously injured by intravenous injection of subarthropathic dose of PG-APS. Twenty-six days later, rats were administered intramuscularly with either vehicle or with AAV-TNFR:Fc vector pseudotyped with AAV type 1 capsid at a dose of 1E12 DNase-resistant particles (DRP). Four weeks post-vector administration, the mean levels of circulating TNFR:Fc protein was 21.5 μg/mL. PG-APS was then administered intravenously to induce a recurring flare of joint inflammation. As expected, animals that were treated with vehicle developed a significant flare of inflammation in their ankle joints. In contrast, the inflammatory response, measured by joint volume, was completely suppressed in AAV2/1-TNFR:Fc-treated animals. To assess the long-term effect of TNFR:Fc expression on suppression of arthritis in this model, animals are currently being evaluated for another round of remission and reactivation of joint inflammation.
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