Research of molecular biology and gene therapy for Rheumatoid arthritis by regulation of IL-6 signal transduction

点击翻译按钮获取中文摘要

Interleukine 6 (IL-6) is one of the inflammatory active indexes in rheumatoid arthritis (RA) patients. A massive clinical trial using a humanized anti-IL-6 receptor antibody (MRA), involving 29 institutes under the organization of Osaka University, has provedn that IL-6 signal blocking by MRA is an efficacious treatment for RA. We have also verified two critical mechanisms for the anti-IL-6 receptor therapy. One is anti-angiogenic activity in synoviocytes by means of the inhibition of IL-6-induced vascular endothelial growth factor (VEGF) production, and the other is preventing the destruction of bone and cartilage by inhibiting IL-6-induced matrix metalloproteinase (MMP) over-production. We have found that IL-6, synergistically with IL-1 and TNF α, up-regulates VEGF and MMP production and therefore plays a pivotal role. The anti-IL-6 treatment appeared most efficacious for the suppression of VEGF and MMP in RA patients. Augmentation of VEGF production induced by IL-6 was observed in n … More ormal fibroblasts, synovial fibroblasts obtained from OA patients as well as RA. We also found that IL-6 induced VEGF production in malignant mesothelioma cells.We established secondary amyloidosis mouse models by virtue of the administration of amyloid enhancing factor (AEF) to the IL-6 transgenic mouse. The treatment of an anti-mouse IL-6 receptor antibody mitigated the amyloidosis in these mouse models, which means that IL-6 is an essential molecule for the development of secondary amyloidosis.SOCS1 and SOCS3, negative regulators of IL-6 cytokine signal, are available for the therapeutic agents as anti-IL-6 therapy. We evaluated optimal gene transfer conditions to achieve the effective expression of SOCS. Although the adenovirus has shown low infectivity to fibroblasts, infectivity enhanced adenoviruses having RGD motifs in their fiber region acquired high infectivity to the synovial fibroblasts and overcame this disadvantage. We also replaced the universal promoter (CMV) with inflammation specific promoters for the control of the transgene expression in RA synovial fibroblasts.We generated a single chain recombinant antibody comprising human IgG1 Fc genetically fused to a single chain Fv derived from the parent antibody MRA. This molecule successfully reduced the IL-6-dependent cell growth and inhibited the phosphorylation of STAT3 induced by IL6 stimulation. This therapeutic agent, encoded on single gene, is easily applicable to the viral gene transfer method. This molecule should be a potential device for the anti-IL-6 therapy combined with the gene therapy method. Less