Gallichan W S, Balasa B, Davies J D, Sarvetnick N
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
J Immunol. 1999 Aug 1;163(3):1696-703.
When immunological tolerance breaks down, autoimmune destruction of insulin-producing beta cells in the pancreas can cause insulin-dependent diabetes mellitus. We previously showed that transgenic nonobese diabetic (NOD) mice expressing IL-4 in the pancreas (NOD-IL-4 mice) were protected from insulitis and diabetes. Here we have characterized the avoidance of pathological autoimmunity in these mice. The absence of disease did not result from a lack of T cell priming, because T cells responding to dominant islet Ags were present. These islet Ag-specific T cells displayed a Th2 phenotype, indicating that Th2 responses could account for the observed tolerance. Interestingly, islet Ag-specific Th1 T cells were present and found to be functional, because neutralization of the Th2 effector cytokines IL-4 and IL-10 resulted in diabetes. Histological examination revealed that NOD-IL-4 splenocytes inhibited diabetogenic T cells in cotransfer experiments by limiting insulitis and delaying diabetes. Neutralization of IL-4 in this system abrogated the ability of NOD-IL-4 splenocytes to delay the onset of diabetes. These results indicate that IL-4 expressed in the islets does not prevent the generation of pathogenic islet responses but induces islet Ag-specific Th2 T cells that block the action of diabetogenic T cells in the pancreas.
当免疫耐受被打破时，胰腺中产生胰岛素的β细胞的自身免疫性破坏可导致胰岛素依赖型糖尿病。我们之前表明，在胰腺中表达白细胞介素-4（IL-4）的转基因非肥胖糖尿病（NOD）小鼠（NOD-IL-4小鼠）可免受胰岛炎和糖尿病的影响。在此，我们对这些小鼠避免病理性自身免疫的机制进行了特征描述。疾病的缺失并非由于缺乏T细胞致敏，因为存在对主要胰岛抗原产生反应的T细胞。这些胰岛抗原特异性T细胞表现出Th2表型，表明Th2反应可能是观察到的耐受性的原因。有趣的是，胰岛抗原特异性Th1 T细胞也存在且具有功能，因为中和Th2效应细胞因子IL-4和IL-10会导致糖尿病。组织学检查显示，在共转移实验中，NOD-IL-4脾细胞通过限制胰岛炎和延缓糖尿病来抑制致糖尿病T细胞。在该系统中中和IL-4消除了NOD-IL-4脾细胞延缓糖尿病发病的能力。这些结果表明，胰岛中表达的IL-4并不能阻止致病性胰岛反应的产生，而是诱导胰岛抗原特异性Th２ T细胞，这些细胞可阻断胰腺中致糖尿病T细胞的作用。
