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首页> 外文期刊>Clinical and experimental allergy : >4-1 BB stimulation inhibits allergen-specific immunoglobulin E production and airway hyper-reactivity but partially suppresses bronchial eosinophilic inflammation in a mouse asthma model.
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4-1 BB stimulation inhibits allergen-specific immunoglobulin E production and airway hyper-reactivity but partially suppresses bronchial eosinophilic inflammation in a mouse asthma model.

机译：4-1 BB刺激抑制了小鼠哮喘模型中过敏原特异性免疫球蛋白E的产生和气道高反应性，但部分抑制了支气管嗜酸性粒细胞的炎症。

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摘要

BACKGROUND: 4-1 BB, a member of the tumour necrosis factor receptor superfamily, functions as a co-stimulatory molecule. Recently, stimulation of the 4-1 BB pathway was shown to suppress antigen-specific CD4(+) T cell and subsequent T cell-dependent humoral immune responses. OBJECTIVE: We examined the effect of agonistic anti-4-1 BB monoclonal antibody (mAb) treatment on allergic asthma, in which allergen-specific type 2 helper T cells (Th2) have been shown to play an important role. METHODS: BALB/c mice were systemically sensitized with intraperitoneal injections of ovalbumin (OVA) and alum on days 0 and 14, and then challenged with inhaled OVA on days 28, 29 and 30. In test groups, the agonistic anti-4-1 BB mAb was administered at the time of initial systemic sensitization with OVA. On day 31, mice were challenged with inhaled methacholine, and enhanced pause was measured as an index of airway hyper-responsiveness (AHR). Levels of OVA-specific IgE in serum, and levels of various cytokines in bronchoalveolar lavage (BAL) fluids were measured. The severity of airway inflammation was determined by differential cell counts in BAL fluids and histopathologic lung analysis. To evaluate local immunity, we cultured lymphocytes from draining perihilar lymph nodes and evaluated the proliferative response to OVA and the levels of IL-5 in the culture supernatant. In addition, the functional mechanism of 4-1 BB stimulation was evaluated in splenocytes obtained at day 7 after systemic OVA sensitization. RESULTS: We found that treatment with the anti-4-1 BB mAb significantly decreased AHR and the production of allergen-specific IgE. Bronchial inflammation, however, had only partially improved and the levels of IL-4 and IL-5 in BAL fluids showed only a small degree of reduction compared with the control Ig-treated mice. Thoracic lymphocytes from anti-4-1 BB-treated mice showed significant suppression of OVA-induced proliferation and IL-5 production. In anti-4-1 BB-treated mice, splenocytes exhibited poor proliferation and marked apoptosis 7 days after systemic OVA challenge. CONCLUSION: These results suggest that stimulation of the 4-1 BB pathway effectively suppresses some features of allergic asthma, including allergen-specific IgE production and AHR, through deletion of allergen-specific Th2 cells. However, we found that bronchial allergic inflammation was not strictly mediated by suppression of the Th2 immune response in this murine model of asthma. Despite these somewhat contradictory effects, intervention in the 4-1 BB pathway might provide a potential novel immunotherapeutic approach for treatment of allergic asthma.
机译：背景：4-1 BB是肿瘤坏死因子受体超家族的成员，起着共刺激分子的作用。最近，对4-1 BB途径的刺激显示可抑制抗原特异性CD4（+）T细胞和随后的T细胞依赖性体液免疫反应。目的：我们研究了抗4-1 BB激动剂单克隆抗体（mAb）对过敏性哮喘的治疗作用，其中已证明过敏原特异性2型辅助T细胞（Th2）起着重要作用。方法：在第0天和第14天通过腹膜内注射卵清蛋白（OVA）和明矾对BALB / c小鼠进行全身致敏，然后在第28、29和30天用吸入的OVA攻击。在试验组中，使用抗4-1激动剂在初次使用OVA进行系统致敏时给予BB mAb。在第31天，用吸入的乙酰甲胆碱攻击小鼠，并测量增强的停顿作为气道高反应性（AHR）的指标。测量血清中OVA特异性IgE的水平，以及支气管肺泡灌洗（BAL）液中各种细胞因子的水平。气道炎症的严重程度由BAL液中的差异细胞计数和组织病理学肺部分析确定。为了评估局部免疫力，我们从排泄的肺门周围淋巴结中培养了淋巴细胞，并评估了对OVA的增殖反应以及培养上清液中IL-5的水平。另外，在全身OVA致敏后第7天获得的脾细胞中评估了4-1 BB刺激的功能机制。结果：我们发现抗4-1 BB mAb治疗显着降低了AHR和过敏原特异性IgE的产生。但是，与对照Ig处理的小鼠相比，支气管炎症仅部分改善，BAL液中IL-4和IL-5的水平仅表现出很小程度的降低。来自抗4-1 BB处理的小鼠的胸淋巴细胞显示出OVA诱导的增殖和IL-5产生的显着抑制。在抗4-1 BB处理的小鼠中，在全身性OVA攻击后7天，脾细胞显示出较弱的增殖和明显的凋亡。结论：这些结果表明，4-1 BB途径的刺激通过删除过敏原特异性Th2细胞，有效抑制了过敏性哮喘的某些特征，包括过敏原特异性IgE产生和AHR。但是，我们发现在这种小鼠哮喘模型中，支气管过敏性炎症并非严格通过抑制Th2免疫应答来介导。尽管存在这些矛盾的影响，但对4-1 BB途径的干预可能会提供一种潜在的新颖的免疫疗法来治疗变应性哮喘。

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