Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA.
Arthritis Res Ther. 2009;11(6):R189. doi: 10.1186/ar2888. Epub 2009 Dec 14.
Tumor necrosis factor is a pleiotropic cytokine with potent immune regulatory functions. Although tumor necrosis factor inhibitors have demonstrated great utility in treating other autoimmune diseases, such as rheumatoid arthritis, there are conflicting results in Sjögren's syndrome. The aim of this study was to assess the effect of a locally expressed tumor necrosis factor inhibitor on the salivary gland function and histopathology in an animal model of Sjögren's syndrome.
Using in vivo adeno associated viral gene transfer, we have stably expressed soluble tumor necrosis factor-receptor 1-Fc fusion protein locally in the salivary glands in the Non Obese Diabetic model of Sjögren's syndrome. Pilocarpine stimulated saliva flow was measured to address the salivary gland function and salivary glands were analyzed for focus score and cytokine profiles. Additionally, cytokines and autoantibody levels were measured in plasma.
Local expression of tumor necrosis factor-receptor 1:immunoglobulin G fusion protein resulted in decreased saliva flow over time. While no change in lymphocytic infiltrates or autoantibody levels was detected, statistically significant increased levels of tumor growth factor-beta1 and decreased levels of interleukin-5, interleukin-12p70 and interleukin -17 were detected in the salivary glands. In contrast, plasma levels showed significantly decreased levels of tumor growth factor-beta1 and increased levels of interleukin-4, interferon-gamma, interleukin-10 and interleukin-12p70.
Our findings suggest that expression of tumor necrosis factor inhibitors in the salivary gland can have a negative effect on salivary gland function and that other cytokines should be explored as points for therapeutic intervention in Sjögren's syndrome.
肿瘤坏死因子是一种具有强大免疫调节功能的多效细胞因子。尽管肿瘤坏死因子抑制剂在治疗其他自身免疫性疾病（如类风湿关节炎）方面已经证明了巨大的应用价值，但在干燥综合征中却存在相互矛盾的结果。本研究旨在评估局部表达的肿瘤坏死因子抑制剂对干燥综合征动物模型中唾液腺功能和组织病理学的影响。
我们通过体内腺相关病毒基因转导，在干燥综合征的非肥胖型糖尿病模型的唾液腺中稳定表达可溶性肿瘤坏死因子受体 1-Fc 融合蛋白。通过匹罗卡品刺激唾液流来评估唾液腺功能，并分析唾液腺的焦点评分和细胞因子谱。此外，还测量了血浆中的细胞因子和自身抗体水平。
肿瘤坏死因子受体 1：免疫球蛋白 G 融合蛋白的局部表达导致唾液流量随时间的推移而减少。虽然未检测到淋巴细胞浸润或自身抗体水平的变化，但在唾液腺中检测到肿瘤生长因子-β1 水平显著升高，白细胞介素-5、白细胞介素-12p70 和白细胞介素-17 水平显著降低。相比之下，血浆水平显示肿瘤生长因子-β1 水平显著降低，白细胞介素-4、干扰素-γ、白细胞介素-10 和白细胞介素-12p70 水平显著升高。
我们的研究结果表明，唾液腺中表达肿瘤坏死因子抑制剂可能对唾液腺功能产生负面影响，并且应该探索其他细胞因子作为干燥综合征治疗干预的靶点。
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