Sustained Exogenous Expression of Therapeutic in Levels of IFN-γ Ameliorates Atopic Dermatitis in NC/Nga Mice via Th1 Polarization
Sustained Exogenous Expression of Therapeutic in Levels of IFN-γ Ameliorates Atopic Dermatitis in NC/Nga Mice via Th1 Polarization
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DOI：
10.4049/jimmunol.0900215
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发表时间：
2010-03-01
影响因子：
4.4
通讯作者：
Takakura, Yoshinobu
中科院分区：
文献类型：
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作者：
Hattori, Kayoko;Nishikawa, Makiya;Takakura, Yoshinobu
IFN-γ 体内半衰期短，可以防止细胞因子诱导免疫变化，而免疫变化有利于治疗 Th2 主导疾病，如特应性皮炎。为了检查持续供应的 IFN-γ 是否能有效调节 Th 淋巴细胞亚群的平衡，将编码小鼠 IFN-γ、pCpG-Mu γ 或 pCMV-Mu γ 的质粒载体注射到 NC/Nga 小鼠（人类特应性皮炎模型）的尾静脉中。单次流体动力学注射CpG基序以0.14μg/小鼠的剂量减少pCpG-Muγ，导致血清中IFN-γ的浓度持续，并且该浓度在80天内维持在>300pg/ml。 pCpG-Muy介导的IFN-γ基因转移与IL-12血清浓度增加、IgE产生减少以及IL-4、-5、-10、-13和-17、胸腺和脾脏中活化调节趋化因子的mRNA表达抑制有关。由于载体表达的瞬时性，在接受两次 20 μg pCMV-Mu gamma（一种 CpG 充足的质粒 DNA）注射的小鼠中，没有清楚地观察到这些免疫学变化。接受 pCpG-Mu gamma 治疗的小鼠表现出皮肤损伤的严重程度和抓挠行为的强度显着降低。此外，未治疗小鼠中明显的大量经表皮失水、表皮增厚以及淋巴细胞和嗜酸性粒细胞浸润均受到显着抑制。这些结果表明，异常持续的 IFN-γ 表达可诱导有利的免疫学变化，导致特应性皮炎模型中的 Th1 主导状态。免疫学杂志，2010，184：2729-2735。
The short in vivo half-life of IFN-gamma can prevent the cytokine from inducing immunological changes that are favorable for the treatment of Th2-dominant diseases, such as atopic dermatitis. To examine whether a sustained supply of IFN-gamma is effective in regulating the balance of Th lymphocyte subpopulations, plasmid vector encoding mouse IFN-gamma, pCpG-Mu gamma, or pCMV-Mu gamma was injected into the tail vein of NC/Nga mice, a model for human atopic dermatitis. A single hydrodynamic injection of a CpG motif reduced pCpG-Mu gamma at a dose of 0.14 mu g/mouse resulted in a sustained concentration of IFN-gamma in the serum, and the concentration was maintained at >300 pg/ml over 80 d. The pCpG-Muy-mediated IFN-gamma gene transfer was associated with an increase in the serum concentration of IL-12, reduced production of IgE, and inhibition of mRNA expression of IL-4, -5, -10, -13, and -17 and thymus and activation-regulated chemokine in the spleen. These immunological changes were not clearly observed in mice receiving two injections of 20 mu g pCMV-Mu gamma, a CpG-replete plasmid DNA, because of the transient nature of the expression from the vector. The mice receiving pCpG-Mu gamma showed a significant reduction in the severity of skin lesions and in the intensity of their scratching behavior. Furthermore, high transepidermal water loss, epidermal thickening, and infiltration of lymphocytes and eosinophils, all of which were obvious in the untreated mice, were significantly inhibited. These results indicate that an extraordinary sustained IFN-gamma expression induces favorable immunological changes, leading to a Th1-dominant state in the atopic dermatitis model. The Journal of Immunology, 2010, 184: 2729-2735.