Rheumatoid arthritis (RA) synovial tissue(ST) is an aggressive tissue replete with macrophages, lymphocytes, fibroblasts, and newly formed blood vessels. Monocyte/macrophages and fibroblasts are key producers of a number of cytokines thought to be responsible, in large part, for the inflammation and joint destruction found in the RA joint. For Instance, the investigator others have shown that these macrophages are important producers of the pro-inflammatory cytokines interleukin (IL)-8, monocyte chemo-attractant protein-1 (MCP-1), and growth related gene product gro-alpha. These cytokines act in concert to mediate Inflammation, in some cases angiogenesis (see Koch, et al., Science 1798, 1992), and the resultant joint destruction. While there are a number of existing therapies for RA, in many patients the disease process still is very severe, resulting in joint destruction, debilitation, and deformity. Mitigating cytokine production may help treat the disease process. In this proposal the applicants will examine the potential of two related antiinflammatory cytokines, IL-4 and IL-13 to downregulate inflammation using a gone therapy approach. IL-4 is a potent inhibitor of angiogenesis as well. Moreover, IL-4 and IL-13 have been shown to have a ben beneficial effect on an animal model of arthritis. The applicants will determine whether they can modulate both the course of pro-inflammatory cytokine production and arthritis in a rat adjuvant-induced arthritis model. They will initially optimize the gene delivery system using adenoviral vectors bearing lacZ. Finally, they will determine whether adenoviral vectors, bearing IL-4 or IL-13, mitigate RA inflammation and cytokine production in an RA ST-severe combined immunodeficient (SCID) mouse chimera. Additionally, this work, it is hoped, will lead to a better understanding of the requirements for gene therapy in RA with other anti-inflammatory genes. The applicants hope that use of gene therapy employing IL-4 or IL-13 genes will result in a promising new therapy for RA, which afflicts many patients each year.
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