Rheumatoid arthritis (RA) is a chronic debilitating disease of the joints characterized by synovial proinflammatory cytokines, bony destruction and angiogenesis. In the ongoing project, we have presented evidence that the """"""""anti-inflammatory""""""""cytokines interleukin (IL)-4 or IL-13 are effective therapeutics when administered via an adenoviral vector approach in 1) rat adjuvant-induced arthritis (AIA), a model for RA and 2) human RA synovial tissue (ST) explant cultures. In rat AIA, these cytokines resulted in a lesser degree of arthritis, decreased synovial proinflammatory monokines, and decreased numbers of ST blood vessels. Similarly, in the RA ST explant model, IL-4 or IL-13 treatment resulted in decreased proinflammatory cytokine production. In the current proposal, we plan to build on our initial observations. Specifically, we will examine whether IL-4 or IL-13 result in decreased 1) angiogenesis, 2) chemokine and chemokine receptor expression, and 3) decreased markers of bone and cartilage destruction in rat AIA. To begin to discern the mechanisms by which IL-4 and IL-13 act, we will define the cellular signaling pathways through which IL-4 and IL-13 mediate their effects on rat AIA joints and on human monocytes and RA synovial fluid monocytes. To further examine the relevance of these cytokines in human systems, we will use RA ST explants to determine whether virally delivered IL-4 or IL-13 inhibit RA ST angiogenesis, chemokine receptor expression, and markers of cartilage and bone destruction. Finally, we will use an RA ST-severe combined mmunodeficiency (SCID) chimera to determine the effects of virally delivered IL-4 or IL-13 on RA ST inflammation and angiogenesis. Cytokine modulation for RA was a mere hope a few years ago. Currently it is a reality for patient care. The experiments proposed in this study should indicate the feasibility of IL-4 and IL-13 as new therapeutics for RA and explore the mechanisms by which they act in RA.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-GMA-1 (01))
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Johnson, David R
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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