Bronchial asthma using a murine model of the disease

我们利用哮喘的小鼠模型研究了诱导Th2细胞免疫耐受是否可以改善哮喘。首先，分析了抑制性T细胞对Th2细胞的抑制作用。我们发现，气管内高剂量的抗原可以诱导分泌转化生长因子-β的CD4T细胞，从而抑制呼吸道嗜酸性粒细胞。这一结果表明，暴露于高剂量抗原并没有导致呼吸道炎症反应的加剧，而是通过激活调节性CD4T细胞来诱导免疫耐受，从而避免了破坏性炎症。分泌转化生长因子-β的新型调节性CD4T细胞可以作为一种可能的治疗工具，因为调节性T细胞的激活可以抑制Th2型细胞和随后的呼吸道炎症。当两种T细胞具有相同的抗原特异性时，Th1细胞有效地抑制Th2细胞。我们以前观察到，如果抗原与细菌一起免疫，强烈诱导Th1的病原体结核分枝杆菌可以诱导抗原特异的Th1细胞。为了扩大我们的观察范围，我们引入了CpG ODN，据报道它可以模拟结核分枝杆菌的Th1诱导活性。CpG与Ag混合免疫可诱导Th1细胞，CpG与Ag的结合可使CpG的免疫效果提高100倍。当CpG与Ag偶联时，CpG对气道嗜酸性粒细胞反应的抗炎作用也增加了100倍。这些效应与诱导区域淋巴结中抗原特异性Th2细胞耐受有关。有趣的是，CpG-Ag结合物对哮喘的治疗作用至少持续了8周。这些观察突出了CpG结合的过敏原作为一种可能有希望的疫苗治疗支气管哮喘的有益方面。

We investigated whether the induction of immune tolerance of Th2 cells could ameliorate bronchial asthma using a murine model of the disease. First, we analyzed the inhibition of Th2 cells by suppressor T cells. We found that high doses of antigen in the trachea could induce TGF-β-secreting CD4 T cells that inhibited airway eosinophilia. This result indicate that exposure to high doses of antigen did no result in the exacerbation of inflammatory responses in the airway, but rather avoid destructive inflammation by inducing immune tolerance through the activation of the regulatory CD4 T cells. The novel regulatory CD4 T cells secreting TGF-β could be used as a possible therapeutic tool, because the activation of the regulatory T cells would inhibit Th2 cells and the subsequent airway inflammation.Another regulatory T cells are Th1 cells. Th1 cells inhibited Th2 cells efficiently when two types of T cells share the antigen specificity. We previous observed that strong Th1-inducing pathogen, Mycobacterium tuberculosis, could induce Ag-specific Th1 cells if the Ag was immunized together with the bacilli. To extend our observations, we introduced CpG ODN that had been reported to mimic the Th1-inducing activity of M. tuberculosis. Immunization with the mixture of CpG and Ag induced Th1 cells, and the conjugation of CpG and Ag enhanced CpG's effects by 100-fold. Anti-inflammatory effects of CpG on airway eosinophilic responses were also augmented by 100-fold when CpG was conjugated to the Ag. These effects were associated with the induction of Ag-specific Th2 cell tolerance in the regional lymph nodes. Interestingly, the effects of CpG-Ag conjugates as therapeutic reagents to bronchial asthma lasted at least for 8 weeks. These observations highlight the beneficial aspects of CpG-conjugated allergen as a possible promising vaccine to treat bronchial asthma.