Agrawal Devendra K, Edwan Jehad, Kandimalla Ekambar R, Yu Dong, Bhagat Lakshmi, Wang Daqing, Agrawal Sudhir
Medical Microbiology and Immunology and Biomedical Sciences, Center for Allergy, Asthma and Immunology, Creighton University School of Medicine, Omaha, NE 68178, USA.
Int Immunopharmacol. 2004 Jan;4(1):127-38. doi: 10.1016/j.intimp.2003.11.005.
Oligodeoxynucleotides containing unmethylated CpG motifs (CpG oligos) have been shown to prevent development of allergic airway inflammation and airway hyperresponsiveness (AHR) in mouse models of asthma. Recently, we reported immunomodulatory oligonucleotides (IMOs) containing novel structures (immunomers) and synthetic immunostimulatory CpR (R=2'-deoxy-7-deazguanosine) motifs show potent stimulatory activity with distinct cytokine secretion profiles. Since type 2 T cells predominate in asthma and increase in type 1 cells can prevent the differentiation of naïve T lymphocytes to a type 2 phenotype, we hypothesized that IMOs can prevent the development of allergic airway inflammation and AHR in the ovalbumin (OVA)-sensitized and challenged mouse model. We found that co-administration of novel IMOs during OVA-sensitization abrogated both early and late allergic responses (LARs). AHR to methacholine was also blocked with IMO treatment. Analysis of bronchoalveolar lavage (BAL) fluid of mice treated with IMOs demonstrated complete reduction in eosinophils, with concomitant decreases in both serum and BAL fluid IL-4, IL-5, and IL-6 levels. In addition, there was a significant reduction in serum IL-10 levels. IMOs, in general, significantly attenuated the rise in serum IgE levels. In comparison, IMOs showed a significantly more potent effect on early and late allergic response than a conventional CpG oligo in this model. These data suggest that the treatment with these novel IMOs prevents OVA-induced allergic airway inflammation and AHR in asthma in the mouse and may provide a useful agent in the treatment of human asthma.
含未甲基化CpG基序的寡脱氧核苷酸（CpG寡核苷酸）已被证明可预防哮喘小鼠模型中过敏性气道炎症和气道高反应性（AHR）的发展。最近，我们报道了含有新型结构（免疫体）和合成免疫刺激CpR（R = 2'-脱氧-7-脱氮鸟苷）基序的免疫调节寡核苷酸（IMO）具有强大的刺激活性，并具有独特的细胞因子分泌谱。由于2型T细胞在哮喘中占主导地位，而1型细胞的增加可阻止幼稚T淋巴细胞分化为2型表型，我们推测IMO可预防卵清蛋白（OVA）致敏和激发的小鼠模型中过敏性气道炎症和AHR的发展。我们发现，在OVA致敏期间共同给予新型IMO可消除早期和晚期过敏反应（LAR）。IMO治疗也可阻断对乙酰甲胆碱的AHR。对用IMO治疗的小鼠支气管肺泡灌洗（BAL）液的分析表明，嗜酸性粒细胞完全减少，同时血清和BAL液中IL-4、IL-5和IL-6水平均降低。此外，血清IL-10水平显著降低。一般来说，IMO可显著减弱血清IgE水平的升高。相比之下，在该模型中，IMO对早期和晚期过敏反应的作用比传统CpG寡核苷酸显著更强。这些数据表明，用这些新型IMO治疗可预防小鼠哮喘中OVA诱导的过敏性气道炎症和AHR，并可能为人类哮喘的治疗提供一种有用的药物。
