Bronchial asthma using a murine model of the disease

我们用小鼠模型研究了诱导Th2细胞的免疫耐受是否可以改善支气管哮喘。首先，我们分析了抑制性T细胞对Th2细胞的抑制作用。我们发现气管内高剂量抗原可诱导分泌TGF-β的CD4 T细胞抑制气道嗜酸性粒细胞增多。这一结果表明，暴露于高剂量的抗原不会导致气道炎症反应的加剧，而是通过激活调节性CD4 T细胞诱导免疫耐受来避免破坏性炎症。新的调节性CD4 T细胞分泌TGF-β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细胞和随后的气道炎症。另一种调节性T细胞是Th1细胞。当两种T细胞共享抗原特异性时，Th1细胞有效抑制Th2细胞。我们之前观察到，如果将Ag与结核分枝杆菌一起免疫，强Th1诱导病原体结核分枝杆菌可以诱导Ag特异性Th1细胞。为了扩展我们的观察，我们引入了CpG ODN，该CpG ODN已被报道可以模拟结核分枝杆菌的th1诱导活性。CpG和Ag混合免疫诱导Th1细胞，CpG和Ag的结合使CpG的作用增强了100倍。当CpG与Ag结合时，CpG对气道嗜酸性粒细胞反应的抗炎作用也增加了100倍。这些作用与局部淋巴结中ag特异性Th2细胞耐受的诱导有关。有趣的是，CpG-Ag偶联物作为支气管哮喘治疗剂的作用至少持续8周。这些观察结果突出了cpg共轭过敏原作为治疗支气管哮喘的一种可能的有前途的疫苗的有益方面。

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.