| Budget Amount *help |
¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 1998: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1997: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Research Abstract |
The development of pannus tissue and the subsequent joint destruction is the most characteristic feature of rheumatoid arthritis. We have developed a new technique to obtain single cell suspensions of synovial tissue-infiltrating cells from rheumatoid synovial tissues without enzyme treatment and have established an in vitro model for human proliferative synovitis, in which synovial tissue-infiltrating cells show macroscopic growth of pannus-like tissue in vitro. The pannus-like tissue growth was inhibited in a dose-dependent manner by gold salt, MTX, anti-TNF-alpha mAb(cA2), leflunomide, while it was not inhibited by indomethacin, NS-398 and anti-CD4 mAbs. Injection of the synovial tissue-infiltrating cells into knee joints resulted in the development of pannus tissue and joint destruction in SCID.bg and Rag2-knockout mice at a high incidence of 65% and 100%, respectively. These results indicated the relevance of the model for the analysis of the pathogenesis and the screening of new
… More
therapeutic agents for rheumatoid arthritis.
The study using both in vivo and in vivo models showed that synovial macrophages played a critical role on the development of pannus tissue and the subsequent joint destruction, while the majority of T cells infiltrating synovial tissues played a regulatory role. Another study revealed a novel mechanism of MTX-mediated suppression of rheumatoid arthritis by preferentially inhibiting the development and IL-6 production of transformed fibroblastoid cells in rheumatoid synovitis. Furthermore, the development of pannus-tissue and joint destruction was inhibited by PGEs in a dose dependent manner, while they were augmented by indomethacin and cox-2 selective inhibitor, NS 398. The inhibitory effect of PGE was mediated by an increase of intracellular cyclic AMP.Suboptimal doses of PGE1(2-2OnM) plus phosphodiesterase-inhibitors such as pentoxifylline(1-3muM) or rolipram(1-3muM) synergistically inhibited pannus tissue development and TNF-alpha production. These results facilitated us to perform an open-labeled clinical trial using lipo-PGEl plus pentoxifylline. Seven patients with active RA received daily intravenous injection of lipo-PGE1 10mug plus oral pentoxifylline 300mg for 4 weeks. ACR 20% response was observed in 4 out of 7 patients. All 4 responders showed a significant improvement within 2 weeks. There were no toxicities noted. All the responders showed a remarkable flare up of arthritis within two weeks after the cessation of lipo-PGE1 while pentoxifylline was continued. The study further indicates an important regulatory role of PGEs in rheumatoid synovitis and suggests that the augmentation of PGE-mediated cyclic AMP signaling is an effective strategy for the treatment of RA. Less
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