Department of Vascular and Thyroid Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Int J Immunopathol Pharmacol. 2012 Apr-Jun;25(2):397-406. doi: 10.1177/039463201202500209.
Orally administered immunomodulatory drugs have recently demonstrated the ability to induce an oral tolerance via inhibition of effector T cells and induction of certain subsets of regulatory T cells (Tregs) which have the potential to prevent several autoimmune diseases. In the present study, we hypothesized that short-term, low-dose, oral FTY720 administration may induce latency-associated peptide (LAP) Tregs and CD4(+) Foxp3(+) Tregs in atherogenesis, potentially resulting in remission of early development of atherosclerosis in apolipoprotein E-deficient (APOE(-/-)) mice. FTY720 was orally administered to APOE(-/-) mice 4 weeks of age on a high-cholesterol diet and atherosclerosis was assessed at 8 weeks of age. Oral administration of FTY720 significantly reduced atherosclerotic lesion formation compared with control mice. We observed a significant increase in LAP(+) and Foxp3(+) cells in the CD4+T-cell population of FTY720-treated mice in association with increased production of the anti-inflammatory cytokine transforming growth factor-β (TGF-β) as well as suppressed T-helper type 1 immune responses. Our findings reveal that short-term, low-dose oral FTY720 treatment had great benefits in inhibiting early development of atherosclerosis in mice via induction of a regulatory T-cell response and inhibition of effector T responses. These findings suggest that oral immune modulation may represent an attractive therapeutic approach to atherosclerosis.
口服免疫调节药物最近已证明具有通过抑制效应 T 细胞和诱导某些调节性 T 细胞（Tregs）亚群来诱导口服耐受的能力，而这些 Tregs 具有预防几种自身免疫性疾病的潜力。在本研究中，我们假设短期、低剂量口服 FTY720 给药可能会在动脉粥样硬化形成中诱导潜伏相关肽（LAP）Tregs 和 CD4(+)Foxp3(+)Tregs，从而可能导致载脂蛋白 E 缺陷（APOE(-/-)）小鼠早期动脉粥样硬化发展的缓解。FTY720 在 APOE(-/-) 小鼠 4 周龄时给予高胆固醇饮食，并在 8 周龄时评估动脉粥样硬化。与对照组相比，FTY720 的口服给药显著减少了动脉粥样硬化病变的形成。我们观察到 FTY720 治疗小鼠的 CD4+T 细胞群中 LAP(+)和 Foxp3(+)细胞显著增加，同时抗炎细胞因子转化生长因子-β（TGF-β）的产生增加，以及辅助性 T 细胞 1 型免疫应答受到抑制。我们的研究结果表明，短期、低剂量口服 FTY720 治疗通过诱导调节性 T 细胞反应和抑制效应 T 细胞反应，对抑制小鼠早期动脉粥样硬化的发展具有很大益处。这些发现表明，口服免疫调节可能代表一种有吸引力的动脉粥样硬化治疗方法。
