Department of Pharmaceutics, University of Florida, Gainesville, FL 32610, USA.
J Gene Med. 2010 Jan;12(1):35-44. doi: 10.1002/jgm.1409.
Rheumatoid arthritis (RA) is a complex disease characterized by autoimmune inflammation and joint destruction. Despite recent advances in RA treatment, current therapies require further improvement to overcome adverse events and ineffectiveness in some cases. By targeting different pathways/molecules using drug combinations, a better treatment can be obtained, whereas adverse events are reduced. In order to develop a new treatment option, the present study employs a gene therapy-based combination therapy using doxycycline and human alpha-1 antitrypsin (hAAT).
DBA/1 mice were immunized with type II collagen to induce arthritis. Four weeks before immunization, they received a doxycycline containing diet and a single injection of adeno-associated virus vector expressing hAAT under the control of a tetracycline-dependent promoter. Control groups received doxycycline alone or saline. Macroscopic arthritis development as well as histopathological changes in the joint were evaluated. In addition, the effects of hAAT and doxycycline on lipopolysaccharide (LPS)- or tumor necrosis factor-alpha-induced interleukin (IL)-6 production from mouse fibroblast cells were also determined.
Combination therapy significantly reduced arthritis development and progression compared to the control group in respect to macroscopic as well as histopathological changes. Doxycycline and hAAT in combination also inhibited IL-6 expression from LPS-stimulated NIH/3T3 mouse fibroblast cells, indicating a contributing mechanism of arthritis inhibition.
The results obtained in the present study indicate that a combination therapy using AAT and doxycycline holds promising potential as a new therapy for RA.
类风湿关节炎（RA）是一种复杂的疾病，其特征为自身免疫炎症和关节破坏。尽管 RA 治疗取得了最近的进展，但目前的治疗方法需要进一步改进，以克服某些情况下的不良反应和无效性。通过使用药物组合靶向不同的途径/分子，可以获得更好的治疗效果，同时减少不良反应。为了开发新的治疗选择，本研究采用基于基因治疗的联合治疗方法，使用强力霉素和人α-1 抗胰蛋白酶（hAAT）。
用 II 型胶原免疫 DBA/1 小鼠以诱导关节炎。在免疫前 4 周，它们接受含有强力霉素的饮食和单次注射腺相关病毒载体，该载体在四环素依赖性启动子的控制下表达 hAAT。对照组接受单独的强力霉素或生理盐水。评估关节炎的宏观发展以及关节的组织病理学变化。此外，还确定了 hAAT 和强力霉素对脂多糖（LPS）或肿瘤坏死因子-α诱导的小鼠成纤维细胞白细胞介素（IL）-6 产生的影响。
与对照组相比，联合治疗在宏观和组织病理学变化方面均显著降低了关节炎的发展和进展。强力霉素和 hAAT 的联合还抑制了 LPS 刺激的 NIH/3T3 小鼠成纤维细胞中 IL-6 的表达，表明这是抑制关节炎的一种机制。
本研究的结果表明，AAT 和强力霉素的联合治疗作为 RA 的一种新治疗方法具有很大的潜力。
