A CD1d-dependent antagonist inhibits the activation of invariant NKT cells and prevents development of allergen-induced airway hyperreactivity.
A CD1d-dependent antagonist inhibits the activation of invariant NKT cells and prevents development of allergen-induced airway hyperreactivity.
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DOI：
10.4049/jimmunol.0901208
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发表时间：
2010-02-15
期刊：
影响因子：
--
通讯作者：
Akbari O
中科院分区：
文献类型：
--
作者：
Lombardi V;Stock P;Singh AK;Kerzerho J;Yang W;Sullivan BA;Li X;Shiratsuchi T;Hnatiuk NE;Howell AR;Yu KO;Porcelli SA;Tsuji M;Kronenberg M;Wilson SB;Akbari O
哮喘在西化国家的患病率继续上升，最佳治疗仍然是一个重大的治疗挑战。最近发现CD1d限制性不变NKT(INKT)细胞在诱导动物模型的气道高反应性(AHR)中起关键作用，并与人类哮喘有关。为了验证iNKT细胞靶向治疗过敏性呼吸道疾病的可行性，用卵清蛋白致敏小鼠，并用CD1d结合的脂质拮抗剂二棕榈酰磷脂酰乙醇胺聚乙二醇酯(DPPE-PEG)进行治疗。单次注射DPPE-PEG可阻止OVA攻击时AHR的形成和淋巴细胞在肺内的浸润，但对OVA特异性Th2反应的形成无影响。此外，α-半乳糖基神经酰胺(α-GalCer)鼻腔给药后，DPPE-聚乙二醇可完全阻止AHR的发展。此外，我们还证明了DPPE-聚乙二醇作为α-GalCer的拮抗剂，与α-GalCer竞争结合CD1d。最后，我们发现DPPE-聚乙二醇能完全抑制α-GalCer诱导的iNKT细胞中ERK酪氨酸激酶的磷酸化，这表明DPPE-聚乙二醇能特异性地阻断TCR信号从而激活iNKT细胞。由于iNKT细胞在AHR的发生发展中起关键作用，DPPE-PEG对iNKT激活的抑制为治疗哮喘等iNKT细胞介导的疾病提供了一种新的途径。
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 α-galactosylceramide (α-GalCer) intranasally. Furthermore, we demonstrate that DPPE-PEG acts as antagonist to α-GalCer and competes with α-GalCer for binding to CD1d. Finally, we show that DPPE-PEG completely inhibits the α-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.
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DOI：
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发表时间：
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期刊：
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影响因子：
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