An Abd transgene prevents diabetes in nonobese diabetic mice by inducing regulatory T cells.

Susceptibility to the human autoimmune disease insulin-dependent diabetes mellitus is strongly associated with particular haplotypes of the major histocompatibility complex (MHC). Similarly, in a spontaneous animal model of this disease, the nonobese diabetic (NOD) mouse, the genes of the MHC play an important role in the development of diabetes. We have produced transgenic NOD mice that express the class II MHC molecule I-Ad in addition to the endogenous I-Ag7 molecules in order to study the role of these molecules in the disease process. Although the inflammatory lesions within the islets of Langerhans in the pancreas appear similar in transgenic and nontransgenic animals, transgenic mice develop diabetes with greatly diminished frequency compared to their nontransgenic littermates (10% of transgenic females by 30 weeks of age compared to 45% of nontransgenic females). Furthermore, adoptive transfer experiments show that T cells present in the transgenic mice are able to interfere with the diabetogenic process caused by T cells from nontransgenic mice. Thus, the mechanism by which I-Ad molecules protect mice from diabetes includes selecting in the thymus and/or inducing in the periphery T cells capable of inhibiting diabetes development. IMAGES:

人类自身免疫性疾病胰岛素依赖型糖尿病（insulin-dependent diabetes mellitus）的易感性与主要组织相容性复合体（major histocompatibility complex, MHC）的特定单体型密切相关。同样，在该疾病的自发性动物模型——非肥胖糖尿病（nonobese diabetic, NOD）小鼠中，MHC基因在糖尿病发病进程中发挥重要作用。为研究此类分子在疾病过程中的作用，我们构建了同时表达内源性I-Ag7分子与MHC II类分子I-Ad的转基因NOD小鼠。尽管转基因与非转基因小鼠的胰腺胰岛内炎性病灶外观相似，但转基因小鼠的糖尿病发病率相较于同窝非转基因小鼠显著降低：30周龄时，转基因雌性小鼠发病率为10%，而非转基因雌性小鼠则为45%。此外，过继转移实验表明，转基因小鼠体内的T细胞能够干扰由非转基因小鼠T细胞介导的致糖尿病过程。综上，I-Ad分子保护小鼠免受糖尿病侵害的机制包括在胸腺中筛选和/或在外周诱导可抑制糖尿病发展的T细胞。图像资料：