Hyperlipidemia induces accelerated rejection of cardiac allografts and resistance to tolerance induction using costimulatory molecule blockade in mice due in part to anti-donor Th17 responses and reduced regulatory T cell function. Accelerated rejection in hyperlipidemic mice is also associated with increased serum levels of IL-6. Here, we examined the role of IL-6 in hyperlipidemia-induced accelerated rejection and resistance to tolerance. Genetic ablation of IL-6 prevented hyperlipidemia-induced accelerated cardiac allograft rejection. Using Th17-lineage fate tracking mice, we observed that IL-6 is required to promote the development of anti-donor Th17 lineage cells independently of antigen challenge. In contrast, the frequency of alloreactive T cells producing IL-2 or IFN-γ remained increased in hyperlipidemic IL-6-deficient mice. Ablation of IL-6 overcame hyperlipidemia-induced changes in Tregs, but was not sufficient to overcome resistance to costimulatory molecule blockade induced tolerance. We suggest that accelerated rejection in hyperlipidemic mice results from IL-6 driven anti-donor Th17 responses. While alterations in Tregs were overcome by ablation of IL-6, the reversal of hyperlipidemia-induced changes in Tregs was not sufficient to overcome increased Th1-type anti-donor T cell responses, suggesting that hyperlipidemia induced IL-6-independent effects on recipient immunity prevent tolerance induction.

中文翻译：

---

IL-6在高脂血症诱导的加速排斥反应中的作用

高脂血症会加速心脏同种异体移植物的排斥反应，并在小鼠中使用共刺激分子阻断法诱导耐受性诱导，部分原因是抗供体 Th17 反应和调节性 T 细胞功能降低。高脂血症小鼠的加速排斥反应也与 IL-6 血清水平升高有关。在这里，我们检查了 IL-6 在高脂血症诱导的加速排斥反应和耐受性抵抗中的作用。IL-6 的基因消融可防止高脂血症诱导的加速心脏同种异体移植排斥反应。使用 Th17 谱系命运追踪小鼠，我们观察到需要 IL-6 来独立于抗原攻击来促进抗供体 Th17 谱系细胞的发育。相反，在高脂血症 IL-6 缺陷小鼠中，产生 IL-2 或 IFN-γ 的同种异体反应性 T 细胞的频率仍然增加。IL-6 的消融克服了高脂血症诱导的 Tregs 变化，但不足以克服对共刺激分子阻断诱导的耐受性的抵抗。我们认为高脂血症小鼠的加速排斥反应是由 IL-6 驱动的抗供体 Th17 反应引起的。虽然通过去除 IL-6 克服了 Tregs 的改变，但高脂血症诱导的 Tregs 变化的逆转不足以克服 Th1 型抗供体 T 细胞反应的增加，这表明高脂血症诱导了对受体的 IL-6 非依赖性影响免疫力阻止耐受诱导。