Quattrocchi E, Walmsley M, Browne K, Williams R O, Marinova-Mutafchieva L, Buurman W, Butler D M, Feldmann M
Kennedy Institute of Rheumatology, London, United Kingdom.
J Immunol. 1999 Jul 15;163(2):1000-9.
Collagen-induced arthritis (CIA) is an experimental model of arthritis widely used to dissect the pathogenesis of human rheumatoid arthritis and to identify potential therapeutic targets. Among these, TNF-alpha has been recognized to play an important role. Here we investigate the feasibility and therapeutic efficacy of prolonged blockade of TNF-alpha activity through the adenovirus-mediated gene delivery of a dimeric chimeric human p55 TNFR-IgG fusion protein and compare it to protein therapy in established CIA. A single i.v. administration of the replication-deficient adenovirus yielded microgram serum levels of the chimeric fusion protein and ameliorated CIA for 10 days. Subsequently, benefit was lost and a rebound to greater inflammatory activity was observed despite the continual presence of bioactive TNFR fusion protein. A similar trend was also observed in mice injected directly with comparable amounts of a human TNFR-IgG fusion protein, whereas the administration of a control adenovirus-encoding beta-galactosidase or of a control human IgG1 protein did not significantly affect the disease course. The mechanisms of the rebound of CIA were investigated, and augmented Ab response to collagen type II and TNFR were identified as potential causes. Our results confirm the feasibility of adenovirus-mediated gene delivery of cytokine inhibitors in animal models of autoimmune diseases for investigational purposes and highlight the importance of prolonged studies. Further investigations are needed to optimize ways of exploiting the potential of adenoviral gene therapy in RA.
胶原诱导性关节炎（CIA）是一种广泛用于剖析人类类风湿性关节炎发病机制和确定潜在治疗靶点的关节炎实验模型。其中，肿瘤坏死因子-α（TNF-α）被认为发挥着重要作用。在此，我们研究通过腺病毒介导的二聚体嵌合人p55肿瘤坏死因子受体-IgG融合蛋白基因递送长期阻断TNF-α活性的可行性和治疗效果，并将其与已建立的CIA模型中的蛋白质疗法进行比较。单次静脉注射复制缺陷型腺病毒可产生微克级血清水平的嵌合融合蛋白，并使CIA改善10天。随后，尽管生物活性肿瘤坏死因子受体融合蛋白持续存在，但益处消失，且观察到炎症活性反弹至更高水平。在直接注射相当量人肿瘤坏死因子受体-IgG融合蛋白的小鼠中也观察到类似趋势，而注射编码β-半乳糖苷酶的对照腺病毒或对照人IgG1蛋白对疾病进程没有显著影响。我们研究了CIA反弹的机制，并确定对II型胶原和肿瘤坏死因子受体的抗体反应增强是潜在原因。我们的结果证实了在自身免疫性疾病动物模型中为研究目的进行腺病毒介导的细胞因子抑制剂基因递送的可行性，并强调了长期研究的重要性。需要进一步研究以优化利用腺病毒基因疗法在类风湿性关节炎中的潜力的方法。
