Division of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
J Immunol. 2010 Feb 15;184(4):2107-15. doi: 10.4049/jimmunol.0901208. Epub 2010 Jan 18.
The prevalence of asthma continues to increase in westernized countries, and optimal treatment remains a significant therapeutic challenge. Recently, CD1d-restricted invariant NKT (iNKT) cells were found to play a critical role in the induction of airway hyperreactivity (AHR) in animal models and are associated with asthma in humans. To test whether iNKT cell-targeted therapy could be used to treat allergen-induced airway disease, mice were sensitized with OVA and treated with di-palmitoyl-phosphatidyl-ethanolamine polyethylene glycol (DPPE-PEG), a CD1d-binding lipid antagonist. A single dose of DPPE-PEG prevented the development of AHR and pulmonary infiltration of lymphocytes upon OVA challenge, but had no effect on the development of OVA-specific Th2 responses. In addition, DPPE-PEG completely prevented the development of AHR after administration of alpha-galactosylceramide (alpha-GalCer) intranasally. Furthermore, we demonstrate that DPPE-PEG acts as antagonist to alpha-GalCer and competes with alpha-GalCer for binding to CD1d. Finally, we show that DPPE-PEG completely inhibits the alpha-GalCer-induced phosphorylation of ERK tyrosine kinase in iNKT cells, suggesting that DPPE-PEG specifically blocks TCR signaling and thus activation of iNKT cells. Because iNKT cells play a critical role in the development of AHR, the inhibition of iNKT activation by DPPE-PEG suggests a novel approach to treat iNKT cell-mediated diseases such as asthma.
哮喘的发病率在西方国家持续上升，而最佳治疗方法仍然是一个重大的治疗挑战。最近，发现 CD1d 限制性不变自然杀伤 T(iNKT)细胞在动物模型中诱导气道高反应性(AHR)中发挥关键作用，并与人类哮喘有关。为了测试 iNKT 细胞靶向治疗是否可用于治疗变应原诱导的气道疾病，用 OVA 对小鼠进行致敏，并使用二棕榈酰磷脂酰乙醇胺聚乙二醇(DPPE-PEG)，一种 CD1d 结合脂质拮抗剂进行治疗。DPPE-PEG 单次给药可预防 OVA 攻击时 AHR 和淋巴细胞肺浸润的发生，但对 OVA 特异性 Th2 反应的发展没有影响。此外，DPPE-PEG 在给予α-半乳糖神经酰胺(α-GalCer)鼻内后完全预防 AHR 的发生。此外，我们证明 DPPE-PEG 作为 α-GalCer 的拮抗剂，与 α-GalCer 竞争与 CD1d 结合。最后，我们表明 DPPE-PEG 完全抑制 iNKT 细胞中 α-GalCer 诱导的 ERK 酪氨酸激酶磷酸化，表明 DPPE-PEG 特异性阻断 TCR 信号传导，从而激活 iNKT 细胞。由于 iNKT 细胞在 AHR 的发展中起关键作用，因此 DPPE-PEG 抑制 iNKT 细胞的激活提示了一种治疗 iNKT 细胞介导的疾病(如哮喘)的新方法。
