Vaccinia virus complement control protein ameliorates collagen induced arthritis: Potential implications for therapy of rheumatoid arthritis.

摘要

Deregulated complement activation can damage self-cells and contribute to pathology of diseases, including rheumatoid arthritis (RA). One of the first documented viral immune evasion proteins is the vaccinia virus major secretory protein, which is referred to as the vaccinia virus complement control protein (VCP) because of its structural similarity to the family of complement control proteins (Kotwal and Moss, 1988, Nature, 335:176–178). VCP inhibits both alternative and classical pathway of complement pathway by binding to the third and fourth complement components and by blocking the formation of the C3-convertase as well as by accelerating the decay of the convertase (Kotwal et al., 1990; McKenzie, et al.). In addition, VCP has been shown to cleave C3b in the presence of factor I to iC3b. The 3D crystal structure of VCP is the only known structure for a complement control protein (Murthy et al.). The present study is undertaken to investigate the pharmacokinetic properties of recombinant VCP (rVCP) in mice and study the therapeutic potential of rVCP in collagen-induced arthritis (CIA) - murine model for rheumatoid arthritis.; Arthritis was induced in male DBA/1J mice by injecting 200 μg of bovine type II collagen emulsified in complete Freund's adjuvant by intradermal injection at the base of the tail. Arthritic mice were treated with intraperitoneal injections of rVCP according to one of the following treatment schedules—Two times a day rVCP injection (25mg/kg of animal weight) starting at disease onset (days 9–16), early intervention (days 16–23) and delayed intervention (days 24–31). Inflammation was monitored by already established arthritic scoring. Morphologic appraisals of inflammation, bone damage and integrity of the articular cartilage matrix were studied by histological sections of arthritic hind paws. The initial results show that rVCP blocks inflammation in all three different treatment schedules. Apart from lowering the clinical arthritic scores and inflammation in arthritic mice, rVCP also prevented loss of cartilage matrix proteoglycans. Lesser numbers of infiltrating inflammatory cells were detected in rVCP treated arthritic joints. Immunohistohemical studies of the arthritic joints show that the number of osteoclasts is reduced in rVCP treated arthritic mice. This may be an indirect result of the heparin binding activity of rVCP due to which there is less infiltration of monocytes/macrophages (main precursors of osteoclasts) in joint space of arthritic mice. These data indicate that rVCP not only blocks the inflammation but also inhibits bone erosion. Some of the observed beneficial effects of VCP may also be attributed to the heparin binding ability of rVCP. The effects of truncated rVCP (containing only 2, 3 & 4 domains), which lacks the ability to bind complement, but retains the heparin binding ability on CIA was also investigated. It appears to have no significant beneficial effects on CIA. rVCP treatment also reduced the production of proinflammatory cytokines—IL-6, TNF-α and IL-12 in arthritic mice. In conclusion rVCP shows promise and potential as a therapeutic agent for RA.