Curative effects of CpG DNA administration on scleroderma-like syndrome of Tsk/+mice

紧皮肤（Tsk/+）小鼠自发发展为硬皮病样疾病，其特征为皮肤增生、自身抗体和肺气肿。IL-4是一种典型的Th2细胞因子，已被认为在其发病机制中起重要作用。在这里，我们研究了未甲基化的CpG寡脱氧核苷酸（ODN）的能力，它是Th1细胞因子的有效诱导剂，可以预防Tdk/+小鼠的硬皮病样综合征的发展。CpG ODN给药7次，间隔3周后，1周龄的Tsk/+小鼠皮肤纤维化明显减少，血清抗核抗体水平低。此外，CpG ODN对皮肤纤维化的发展具有长期抑制作用。CpG ODN诱导的IFN-γ产生细胞可能有助于抑制皮肤厚度的发展。但对肺气肿无明显疗效。肺气肿的发生机制可能与Th1/Th2细胞因子的平衡无关。当6周龄的Tsk/+小鼠开始给药CpG ODN时，疾病的发病机制没有改善。这些结果表明，CpG ODN诱导的th1偏向的细胞因子环境可以改善硬皮病样综合征，并支持CpG ODN治疗可能是治疗th2驱动疾病的可行方法。

The tight-skin (Tsk/+) mice spontaneously develop scleroderma-like disease characterized by cutaneous hyperplasia, auto antibodies and pulmonary emphysema. IL-4, a typical Th2 cytokine, has been suggested to play an important role in the pathogenesis.Here, we examined the ability of unmethylated CpG oligodeoxynucleotides (ODN), which are potent inducer of Th1 cytokines, to prevent the development of scleroderma-like syndrome of Tdk/+mice. After 7 times administration of CpG ODN with 3-wk interval into 1-wk old Tsk/+ mice, dermal fibrosis was significantly reduced and low levels of serum antinuclear antibodies were detected. Furthermore, CpG ODN had a long-term inhibitory effect on the development of skin fibroses. IFN-γ producing cells induced by CpG ODN administration might contribute to inhibit the development of skin thickness.However, no curative effect was observed on lung emphysema. The mechanisms of emphysema development could be independent of Th1/Th2 cytokine balance. When CpG ODN administration was started with 6-wk old Tsk/+ mice, the pathogenesis of the disease was not improved.Theses results indicate that a Th1-biased cytokine milieu induced by CpG ODN ameliorate scleroderma-like syndrome, and support that CpG ODN treatment may be a feasible approach in the therapy of Th2-driven diseases.