Zhang Fang, Huang Gang, Hu Bo, Song Yong, Shi Yi
Department of Pulmonary Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China.
Clin Vaccine Immunol. 2011 May;18(5):807-14. doi: 10.1128/CVI.00434-10. Epub 2011 Feb 23.
Allergen-specific immunotherapy is a potential treatment for allergic diseases. We constructed an allergen-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)-encoding DNA vaccine, administered it directly to antigen-presenting cells (APCs), and investigated its ability and mechanisms to ameliorate allergic airway inflammation in an asthmatic mouse model. An allergen-CTLA-4 DNA plasmid (OVA-CTLA-4-pcDNA₃.₁) encoding an ovalbumin (OVA) and the mouse CTLA-4 extracellular domain was constructed and transfected into COS-7 cells to obtain the fusion protein OVA-CTLA-4, which was able to bind the B7 ligand on dendritic cells (DCs), and induced CD25⁺ Foxp3⁺ regulatory T (Treg) cells by the coculture of naive CD4⁺ T cells with DCs in vitro. In an animal study, BALB/c mice were sensitized and challenged with OVA to establish the asthmatic model. Vaccination with a high dose of OVA-CTLA-4-pcDNA₃.₁ significantly decreased interleukin-4 (IL-4) and IL-5 levels and eosinophil counts and prevented OVA-induced reduction of the gamma interferon level in the bronchoalveolar lavage fluid. In addition, these mice suffered less severe airway inflammation and had lower levels of OVA-specific IgE and IgG1 titers in serum. Also, high-dose OVA-CTLA-4-pcDNA₃.₁ vaccination inhibited the development of airway hyperreactivity and prevented OVA-induced reduction of the percentages of Foxp3⁺ Treg cells in the spleen. Our results indicate that a high dose of allergen-CTLA-4-encoding DNA vaccine was more effective in preventing an allergen-induced Th2-skewed immune response through the induction of Treg cells and may be a new alternative therapy for asthma.
变应原特异性免疫疗法是治疗过敏性疾病的一种潜在方法。我们构建了一种编码变应原 - 细胞毒性T淋巴细胞相关抗原4（CTLA - 4）的DNA疫苗，将其直接给予抗原呈递细胞（APC），并在哮喘小鼠模型中研究其改善过敏性气道炎症的能力和机制。构建了一种编码卵清蛋白（OVA）和小鼠CTLA - 4细胞外结构域的变应原 - CTLA - 4 DNA质粒（OVA - CTLA - 4 - pcDNA₃.₁），并将其转染到COS - 7细胞中以获得融合蛋白OVA - CTLA - 4，该融合蛋白能够结合树突状细胞（DC）上的B7配体，并通过体外将未成熟CD4⁺ T细胞与DC共培养诱导产生CD25⁺ Foxp3⁺调节性T（Treg）细胞。在一项动物研究中，用OVA对BALB / c小鼠进行致敏和激发以建立哮喘模型。高剂量的OVA - CTLA - 4 - pcDNA₃.₁疫苗接种显著降低了白细胞介素 - 4（IL - 4）和IL - 5水平以及嗜酸性粒细胞计数，并防止了OVA诱导的支气管肺泡灌洗液中γ干扰素水平的降低。此外，这些小鼠的气道炎症较轻，血清中OVA特异性IgE和IgG1滴度较低。而且，高剂量的OVA - CTLA - 4 - pcDNA₃.₁疫苗接种抑制了气道高反应性的发展，并防止了OVA诱导的脾脏中Foxp3⁺ Treg细胞百分比的降低。我们的结果表明，高剂量的编码变应原 - CTLA - 4的DNA疫苗通过诱导Treg细胞在预防变应原诱导的Th2偏向性免疫反应方面更有效，可能是哮喘的一种新的替代疗法。
