Invariant natural killer T-cell neutralization is a possible novel therapy for human eosinophilic esophagitis
Invariant natural killer T-cell neutralization is a possible novel therapy for human eosinophilic esophagitis
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DOI：
10.1038/cti.2013.13
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发表时间：
2014-01-01
影响因子：
5.8
通讯作者：
Mishra, Anil
中科院分区：
文献类型：
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作者：
Rayapudi, Madhavi;Rajavelu, Priya;Mishra, Anil
嗜酸性粒细胞性食管炎 (EoE) 是最近公认的一种炎症性疾病，需要潜在的治疗策略。我们之前表明 iNKT 细胞缺陷小鼠可以免受过敏原诱导的 EoE 影响。因此，我们现在测试了以下假设：iNKT 细胞在人类 EoE 中被诱导，并且是治疗人类 EoE 的新的可能靶标。因此，我们通过对正常受试者（对照）和 EoE 患者的食管活检和血液样本进行免疫荧光、qPCR 和 ELISA 检测 iNKT 细胞和嗜酸性粒细胞的数量以及 iNKT 相关细胞表面受体和趋化因子的表达。在此，我们发现与正常个体相比，EoE 患者中 iNKT 细胞数量、其受体亚成分 V α 24 和 V β 11 表达以及相关趋化因子 CXCL16 水平（或表达）显着诱导。此外，我们发现 CXCL16 水平（或表达）与 V α 24 受体的 mRNA 水平相关，但与人 EoE 中的食管嗜酸性粒细胞增多相关性不佳。值得注意的是，我们发现 iNKT 细胞的体内激活足以在小鼠中诱导 EoE。此外，我们发现抗 mCD1d 和抗 hV α 24J α 18 中和抗体治疗可保护过敏原诱导的实验性 EoE。综上所述，我们首次证明 iNKT 细胞在人类和实验 EoE 中具有关键的致病作用。通过人源化抗 CD1d 和抗 V α 24J α 18 抗体中和 iNKT 细胞可能是治疗人类 EoE 的一种新颖且潜在的疗法。
Eosinophilic esophagitis (EoE) is a recently recognized inflammatory disorder that needs a potential therapeutic strategy. We earlier showed that iNKT cell-deficient mice are protected from allergen-induced EoE. Therefore, we now tested the hypothesis that iNKT cells are induced in the human EoE and is a novel possible target for the treatment of human EoE. Accordingly, we examine number of iNKT cells and eosinophils and expression of iNKT-associated cell surface receptors and chemokines by performing immunofluorescence, qPCR and ELISA in the esophageal biopsies and blood samples of normal subjects (comparison control) and EoE patients. Herein, we show that iNKT cell number, their receptor subcomponents V alpha 24 and V beta 11 expression, and associated chemokine CXCL16 levels (or expression) are induced significantly in EoE patients compared with normal individuals. In addition, we show that CXCL16 levels (or expression) correlate with the mRNA levels of V alpha 24 receptor but not well with esophageal eosinophilia in human EoE. Of note, we show that in vivo activation of iNKT cells is sufficient to induce EoE in mice. Furthermore, we show that anti-mCD1d-and anti-hV alpha 24J alpha 18-neutralizing antibody treatment protects allergen-induced experimental EoE. Taken together, we have shown first time that iNKT cells have a critical pathogenic role in human and experimental EoE. iNKT cell neutralization by humanized anti-CD1d and anti-V alpha 24J alpha 18 antibodies might be a novel and potential therapy for human EoE.