组胺H4受体在鼻黏膜胸腺基质淋巴细胞生成素介导Th2免疫反应中的调控作用

Regulation of Histamine H4 Acceptor on Th2 Immune Responses Mediated by Thymic Stromal Lymphopoietin in Guinea pigs with Allergic Rhinitis

目的研究组胺H4受体(H4R)在变应性鼻炎(AR)豚鼠鼻黏膜胸腺基质淋巴细胞生成素(TSLP)介导Th2免疫反应中的调控作用。方法将豚鼠随机分为对照组、模型组、治疗组1和治疗组2;模型组和治疗组通过卵清蛋白建立AR模型;对照组以生理盐水代替卵清蛋白。在鼻内激发的最后1周,治疗组1给予H4R拮抗剂(JNJ7777120,JNJ)治疗,治疗组2给予JNJ和抗TSLP单克隆抗体(anti-TSLP)联合治疗。采用Western-blotting检测鼻黏膜OX40配体(OX40L)的表达,ELISA检测鼻腔灌注液中Th2细胞因子(IL-4和13)的含量,病理组织学检测鼻黏膜炎细胞(嗜酸性粒细胞、淋巴细胞、单核细胞)数量。结果与对照组比较,模型组OX40L蛋白、Th2细胞因子含量和炎细胞数量明显上调(P<0.05);经JNJ单独或联合anti-TSLP治疗后上述指标较模型组显著下调,治疗组1与治疗组2组间比较有统计学差异(P<0.05)。结论通过H4R干预调控TSLP/OX40L信号通路活化所诱导的Th2免疫反应,减少Th2细胞因子生成和鼻黏膜炎细胞浸润,可能是AR治疗的新方法。

Objective This study aimed to study the effects of histamine H4 acceptor(H4 R)on Th2 immune responses mediated by thymic stromal lymphopoietin(TSLP)in guinea pigs with allergic rhinitis(AR).Methods Guinea pigs were randomly divided into control group,model group,treated group 1 and treated group 2.AR Model was established in model group,treated group 1 and treated group 2 by sensitization with ovalbumin(OVA)and Al(OH)3 and the nasal challenge with OVA.On the last week,treated group 1 were treated with H4 Rantagonist(JNJ7777120,JNJ),and treated group 2 were treated with JNJ and anti-TSLP monoclonal antibody(anti-TSLP).OX40 ligand(OX40 L)expression in the nasal mucosa was assayed by western blotting.The levels of IL-4 and 13 in nasal lavage fluids were detected by ELISA.The number of inflammatory cells in the nasal mucosa was detected by pathologic histology.Results The expression of OX40 Lprotein,the content of Th2 cytokines and the number of inflammatory cells in model group increased compared to control group(P<0.05).JNJ treatment alone or combined with anti-TSLP treatment led to a significant decrease of these parameters.Conclusion H4 Rinhibition can regulate Th2 immune responses through TSLP/OX40 Lpathway,decrease the production of Th2 cytokines and the infiltration of inflammatory cells in the nasal mucosa,which may be a new way for AR treatment.