Yoh Keigyou, Shibuya Kazuko, Morito Naoki, Nakano Takako, Ishizaki Kazusa, Shimohata Homare, Nose Masato, Izui Shozo, Shibuya Akira, Koyama Akio, Engel James Douglas, Yamamoto Masayuki, Takahashi Satoru
Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan.
J Am Soc Nephrol. 2003 Oct;14(10):2494-502. doi: 10.1097/01.asn.0000086473.23379.25.
A T helper 1 (Th1)/Th2 imbalance is thought to contribute to the pathogenesis of autoimmune diseases. The differentiation of T cells into Th1 or Th2 subtypes is under the regulation of several transcription factors. Among these, transcription factor GATA-3 is thought to play an indispensable role in the development of T cells and the differentiation of Th2 cells. To examine how a Th1/Th2 imbalance affects the development of autoimmune disease, GATA-3 was overexpressed in the T lymphocytes of C57BL/6 x BXSB/MpJ-Yaa F(1) (Yaa) mice. Yaa mice developed autoimmune nephritis similarly to BXSB/MpJ-Yaa mice, which are commonly used as a model for Th1-dominant murine lupus. GATA-3 overexpression in T cells improved the 50% mortality incidence time for GATA-3-transgenic Yaa mice (41.6 wk), compared with Yaa mice (30.9 wk), and reduced proteinuria, serum creatinine levels, and the severity of glomerulonephritis in GATA-3-transgenic Yaa mice. GATA-3 overexpression in Yaa mice led to simultaneously elevated Th2 Ig (IgG1) and decreased Th1 Ig (IgG2a and IgG3) production and serum IFN-gamma levels. Although IL-4 production remained unchanged, intracellular cytokine analyses demonstrated that IL-5 was induced and IFN-gamma was suppressed in stimulated T cells from the GATA-3-transgenic Yaa mice. These results indicated that abundant GATA-3 was unable to stimulate complete differentiation of Th2 cells but did counteract the dominance of Th1 cells and alleviated the disease severity in Yaa mice. These data suggest that transcriptional regulation therapy may have potential as an effective strategy for treating autoimmune glomerulonephritis.
辅助性T细胞1（Th1）/Th2失衡被认为与自身免疫性疾病的发病机制有关。T细胞向Th1或Th2亚型的分化受多种转录因子调控。其中，转录因子GATA-3被认为在T细胞发育和Th2细胞分化过程中发挥不可或缺的作用。为了研究Th1/Th2失衡如何影响自身免疫性疾病的发展，在C57BL/6×BXSB/MpJ-Yaa F(1)（Yaa）小鼠的T淋巴细胞中过表达GATA-3。Yaa小鼠与常用作Th1主导型小鼠狼疮模型的BXSB/MpJ-Yaa小鼠一样，会发生自身免疫性肾炎。与Yaa小鼠（30.9周）相比，T细胞中GATA-3过表达使GATA-3转基因Yaa小鼠的50%死亡率发生时间延长（41.6周），并降低了GATA-3转基因Yaa小鼠的蛋白尿、血清肌酐水平以及肾小球肾炎的严重程度。Yaa小鼠中GATA-3过表达导致Th2型免疫球蛋白（IgG1）同时升高，Th1型免疫球蛋白（IgG2a和IgG3）产生及血清干扰素-γ水平降低。尽管白细胞介素-4的产生保持不变，但细胞内细胞因子分析表明，来自GATA-3转基因Yaa小鼠的受刺激T细胞中白细胞介素-5被诱导，干扰素-γ受到抑制。这些结果表明，大量的GATA-3虽无法刺激Th2细胞完全分化，但确实抵消了Th1细胞的主导作用，并减轻了Yaa小鼠的疾病严重程度。这些数据表明，转录调控疗法可能具有作为治疗自身免疫性肾小球肾炎的有效策略的潜力。
