title: Induction of immune tolerance in asthmatic mice by vaccination with DNA encoding an allergen-cytotoxic T lymphocyte-associated antigen 4 combination.
abstract: 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.
authors.affiliation: Department of Pulmonary Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China. zhangfanglab@yahoo.com.cn
authors.forename: Fang
authors.initials: F
authors.lastname: Zhang
authors.forename: Gang
authors.initials: G
authors.lastname: Huang
authors.forename: Bo
authors.initials: B
authors.lastname: Hu
authors.forename: Yong
authors.initials: Y
authors.lastname: Song
authors.forename: Yi
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000485:Allergens / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D001249:Asthma / Q000473:pathology / Q000628:therapy*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000032:analysis; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D007108:Immune Tolerance; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007167:Immunotherapy / Q000379:methods*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014611:Vaccination / Q000379:methods*; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*
chemical_list: D000485:Allergens; D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D016207:Cytokines; D007074:Immunoglobulin G; D011994:Recombinant Proteins; D019444:Vaccines, DNA; D007073:Immunoglobulin E; D010047:Ovalbumin