Our preliminary studies of synovial tissues samples obtained from patients with juvenile rheumatoid arthritis (JRA) showed increased vascularization and vascular endothelial cell (VEC) activation. These features remained prominent in JRA synovial tissues fragments engrafted in SCID mice, and correlated well with human IL-15 expression. It has been shown that IL-15 is able to activated VEC and promote angiogenesis in some experimental systems. Based on these data, we hypothesize that IL-15 plays a central role in VEC activation and vascularization of the pannus tissue in JRA. To test our hypothesis, we propose to take advantage of highly prominent revascularization in human synovial tissue fragments implanted into SCID mice which should facilitate identification of cytokines most critical to angiogenesis. We propose to block human IL-15 on VEC activation and neovascularization in JRA synovial tissue grants. Subsequently, we ill investigate the effects of reduced IL-15 activity on trafficking of the human inflammatory cells into the engrafted tissues after intravenous reconstitution of the SCID mouse-human synovial tissue chimeras with human syngeneic mononuclear cells. We will also compare the effects of blocking IL-15 with those of blocking TNF-alpha, another pro-inflammatory cytokine with known ability to stimulate endothelial cells. We will then determine the effects of exogenous administration of IL-15 on vascular endothelial cell activation and neovascularization in the JRA synovial tissue fragments engrafted into SCID mice. The demonstration of the ability of IL-15 to enhance the activation of VEC and neovascularization in human JRA tissues, will provide further evidence to support the hypothesis about the central role for IL15 in angiogenesis. The major long-term goal of this study is to elucidate the role of IL-15 IN JRA synovium. If a central role for IL-15 in VEC activation and neovascularization is established, our further studies will focus on elucidation of molecular mechanisms of IL-15 induced VEC activation, and eventually, on designing anti-IL-15 strategies for JRA treatment.
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