Rheumatoid arthritis (RA) is a chronic inflammatory disease that may result in joint destruction mediated by a variety of cells including macrophages. While great advances in therapy have been made, the mechanism of action of effective therapy is poorly understood. However, published studies document that the extent of macrophage infiltration in the synovial tissue is a strong predictor of clinical outcome. Further, examination of synovial tissue biopsies before and after therapy, demonstrate that the reduction of sublining CD68+ macrophages strongly correlates with the reduction of the DAS28, regardless of the therapy. The mechanism by which synovial tissue macrophages are reduced following effective therapy is not known. Potential mechanisms include reduced recruitment of monocytes into the tissue, increased cell death, such as apoptosis, or increased trafficking out of the tissue via the lymphatics to the lymph nodes. An understanding of the responsible mechanism is critical to identify safer, rationally designed, more effective therapy, especially fo those who do not respond adequately to currently available therapy. Studies that examined synovial tissue apoptosis 1, 24 and 48 hours after the initiation of therapy with infliximab, which resulted in significant reduction of synovial tissue macrophages, failed to demonstrate apoptosis employing the gold standard, electron microscopy. Further, employing a technique to directly track the migration of circulating monocytes into RA synovial tissue, no reduction of monocyte migration was observed in patients treated with adalimumab, a therapy that results in rapid reduction of synovial tissue macrophages. Together these observations suggest than neither macrophage apoptosis nor reduction of migration of monocytes into the RA joint is responsible for the clinical response to TNF inhibitors, suggesting a potential role for increased egress of macrophages, and possibly other cell types, from the RA joint as an important mechanism of action. Our preliminary data demonstrate that CCR7 is expressed by RA synovial tissue macrophages. Also we have shown recently that the CCR7 ligands CCL19 and CCL21 are expressed in RA synovial tissue. Further, CCR7, CCL19 and 21 are induced by inflammatory mediators including TNFalpha. Studies in mice with atherosclerosis demonstrate that egress of macrophages from diseased aortas is mediated by CCR7. Additionally, CCR7 deficient mice demonstrate more chronic immune complex mediated arthritis, and the synovitis is highly enriched in macrophages. Therefore, we propose to employ a murine model of arthritis to examine the hypothesis that the mechanism of effective therapy is increased macrophage egress from tissue which is mediated by CCR7. This hypothesis will be tested employing two specific aims: (1) Employing human TNF transgenic mice, determine if the response to treatment with inhibitors of TNF or TNF plus IL-1 will be prevented by the neutralization of CCL19 and CCL21. (2) Employing human TNF transgenic mice, determine if the response to inhibition of TNF or TNF plus IL-1 is mediated by CCR7.