Hung Jung-Tung, Liao Jen-Hsiang, Lin Yu-Chung, Chang Hsiu-Ying, Wu Shu-Fen, Chang Tsung-Hsien, Kung John T, Hsieh Shie-Liang, McDevitt Hugh, Sytwu Huey-Kang
Graduate Institute of Life Sciences, National Defense Medical Center, 161, Section 6, MinChuan East Road, Neihu, Taipei 114, Taiwan.
J Autoimmun. 2005 Nov;25(3):181-92. doi: 10.1016/j.jaut.2005.08.010. Epub 2005 Nov 2.
To improve the feasibility of in vivo monitoring of autoreactive T cells in the diabetogenic process, we generated T1 and T2 doubly transgenic non-obese diabetic (NOD) mice in which transgenic human CD90 (hCD90) is simultaneously expressed on IFN-gamma-producing cells or murine CD90.1 (mCD90.1) is expressed on IL-4-producing cells. These transgenic NOD mice develop diabetes with the same kinetics and incidence as wild type NOD mice, permitting the physiological characterization of CD4(+)hCD90(+) cells, which represent T(H)1 cells in lymphoid organs and at the site of insulitis. CD4(+)hCD90(+) cells had a higher capacity to secret IFN-gamma than CD4(+)hCD90(-) cells in an autoantigen-specific manner. Transgenic mice treated with GAD65 plasmid were protected from autoimmune diabetes, and had a lower number of CD4(+)hCD90(+) cells, confirming the pathogenic role of CD4(+)hCD90(+) cells in autoimmune diabetes. To further investigate the effect of IL-12 on the development of T(H)1 cells in autoimmune diabetes, we crossed these doubly transgenic mice to IL-12p35-deficient NOD mice. Despite severe disturbance of diabetes in p35(-/-) mice, the frequency of T(H)1 cells in these mice was slightly lower than in wild type mice. These data support the pathological role of IL-12 in autoimmune diabetes and suggest the existence an IL-12-independent pathway of T(H)1 development.
为提高在致糖尿病过程中对自身反应性T细胞进行体内监测的可行性，我们构建了T1和T2双转基因非肥胖糖尿病（NOD）小鼠，其中转基因人CD90（hCD90）在产生干扰素-γ的细胞上同时表达，或者小鼠CD90.1（mCD90.1）在产生白细胞介素-4的细胞上表达。这些转基因NOD小鼠患糖尿病的动力学和发病率与野生型NOD小鼠相同，这使得对CD4(+)hCD90(+)细胞进行生理学特征分析成为可能，这些细胞在淋巴器官和胰岛炎部位代表辅助性T细胞1（TH1）。CD4(+)hCD90(+)细胞以自身抗原特异性方式分泌干扰素-γ的能力高于CD4(+)hCD90(-)细胞。用谷氨酸脱羧酶65（GAD65）质粒处理的转基因小鼠可预防自身免疫性糖尿病，且CD4(+)hCD90(+)细胞数量较少，这证实了CD4(+)hCD90(+)细胞在自身免疫性糖尿病中的致病作用。为进一步研究白细胞介素-12对自身免疫性糖尿病中TH1细胞发育的影响，我们将这些双转基因小鼠与白细胞介素-12 p35缺陷型NOD小鼠杂交。尽管p35(-/-)小鼠的糖尿病严重紊乱，但这些小鼠中TH1细胞的频率略低于野生型小鼠。这些数据支持白细胞介素-12在自身免疫性糖尿病中的病理作用，并提示存在一条不依赖白细胞介素-12的TH1发育途径。
