State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
Biomaterials. 2012 Oct;33(30):7605-12. doi: 10.1016/j.biomaterials.2012.06.074. Epub 2012 Jul 15.
Systemic blockade of TNF-α via monoclonal antibodies and soluble receptors has shown considerable effects against several typical autoimmune disorders, but remains unconvincing for the treatment of lupus. Based on our previous study, a CD169(+) macrophage-specific therapy using TNF-α antisense oligonucleotides (ASO) was tested for its efficacy in MRL/lpr lupus-prone mice. ASO-containing cationic agarose hydrogel were injected into mice subcutaneously. Tissue distribution and cellular localization of ASO were determined. The therapeutic effects and possible mechanism were further studied in MRL/lpr lupus-prone mice. The results showed that specifically accumulation of the anti-TNF-α ASO in CD169(+) macrophages could significantly reduce TNF-α expression in CD169(+) macrophages and inhibit lymphocytes over-proliferation, finally resulted in the relief of the lupus-like symptoms of the animals. The nucleic acid drug based on CD169(+) macrophage-specific TNF-α regulation represents a potential therapeutic approach that may be valuable for lupus therapy.
通过单克隆抗体和可溶性受体对 TNF-α 的系统阻断已显示出对几种典型自身免疫性疾病的显著疗效，但对狼疮的治疗仍不令人信服。基于我们之前的研究，使用 TNF-α 反义寡核苷酸 (ASO) 的 CD169(+) 巨噬细胞特异性治疗在 MRL/lpr 狼疮易感小鼠中进行了疗效测试。将含有 ASO 的阳离子琼脂糖水凝胶皮下注射到小鼠中。确定 ASO 的组织分布和细胞定位。进一步研究了 MRL/lpr 狼疮易感小鼠中的治疗效果和可能的机制。结果表明，抗 TNF-α ASO 的特异性积聚在 CD169(+) 巨噬细胞中可显著降低 CD169(+) 巨噬细胞中 TNF-α 的表达，并抑制淋巴细胞过度增殖，最终缓解动物的狼疮样症状。基于 CD169(+) 巨噬细胞特异性 TNF-α 调节的核酸药物代表了一种有希望的狼疮治疗方法。
