Elias D, Tikochinski Y, Frankel G, Cohen I R
Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Int Immunol. 1999 Jun;11(6):957-66. doi: 10.1093/intimm/11.6.957.
NOD mice spontaneously develop type I diabetes resulting from autoimmune destruction of their insulin-producing beta cells. Among the self-antigens targeted by NOD autoimmune T cells is a peptide, p277, from the sequence of the 60 kDa heat shock protein (hsp60). Common to the anti-p277 T cell populations of NOD mice is an idiotope, C9, that spans the CDR3 region of the C9 TCR. We now report: (i) that the C9 idiotope peptide can be presented directly to anti-C9 anti-idiotypic T cells by C9 T cells, (ii) that spontaneous anti-C9 anti-idiotypic T cell activity falls as disease progresses, but immunization can activate the anti-idiotypic T cells to regulate the autoimmune process, (iii) that the anti-idiotypic T cells secrete IFN-gamma, but appear to control the disease by down-regulating the IFN-gamma produced by the pathogenic population of anti-p277 T cells, (iv) that intrathymic administration of the C9 idiotope peptide at 1 week of age can accelerate the disease, and (v) that administering the p277 target peptide can up-regulate the anti-idiotypic T cells and arrest the disease process. Thus, the development of NOD diabetes can be regulated by a balance between anti-idiotypic and anti-target peptide autoimmunity, and anti-idiotypic regulation can lead to changes in the cytokine secretion of the autoimmune T cells involved in the disease process.
非肥胖糖尿病（NOD）小鼠会因自身免疫性破坏其产生胰岛素的β细胞而自发发展为I型糖尿病。NOD自身免疫性T细胞靶向的自身抗原中，有一种来自60 kDa热休克蛋白（hsp60）序列的肽段p277。NOD小鼠的抗p277 T细胞群体共有的一个独特型是C9，它跨越C9 TCR的互补决定区3（CDR3）区域。我们现在报告：（i）C9独特型肽段可由C9 T细胞直接呈递给抗C9抗独特型T细胞；（ii）随着疾病进展，自发的抗C9抗独特型T细胞活性下降，但免疫可激活抗独特型T细胞来调节自身免疫过程；（iii）抗独特型T细胞分泌γ干扰素（IFN-γ），但似乎通过下调致病性抗p277 T细胞群体产生的IFN-γ来控制疾病；（iv）在1周龄时胸腺内给予C9独特型肽段可加速疾病发展；（v）给予p277靶肽可上调抗独特型T细胞并阻止疾病进程。因此，NOD糖尿病的发展可通过抗独特型和抗靶肽自身免疫之间的平衡来调节，且抗独特型调节可导致参与疾病过程的自身免疫性T细胞细胞因子分泌的变化。
