title: T lymphocyte antigen 4-modified dendritic cell therapy for asthmatic mice guided by the CCR7 chemokine receptor.
abstract: The CD80/CD86-CD28 axis is a critical pathway for immuno-corrective therapy, and the cytotoxic T lymphocyte antigen 4 (CTLA4) is a promising immunosuppressor targeting the CD80/CD86-CD28 axis; however, its use for asthma therapy needs further optimization. A human CTLA4 fused with the IgCγ Fc (CTLA4Ig) and mouse CC chemokine receptor type7 (CCR7) coding sequences were inserted into a recombinant adenovirus (rAdV) vector to generate rAdV-CTLA4Ig and rAdV-CCR7. The naive dendritic cells (DCs) were infected with these rAdVs to ensure CCR7 and CTLA4Ig expression. The therapeutic effects of modified DCs were evaluated. rAdV-CTLA4Ig and rAdV-CCR7 infected DCs improved all asthma symptoms. Inflammatory cell infiltration and cytokine analysis showed that rAdV-CTLA4Ig and rAdV-CCR7-modified DC therapy reduced the number of eosinophils and lymphocyte and neutrophil infiltration in the lung. Interestingly, assessment of the humoral immunity showed that the IL-4 and IFNγ levels of the rAdV-CTLA4Ig and rAdV-CCR7-modified DC-treated mice decreased significantly and did not reverse the Th1/Th2 balance. DCs expressing CCR7 displayed guidance ability for DC migration, primarily for DCs in the inflammatory lung. Additionally, the rAdVs caused an inflammatory response by inducing DC differentiation, inflammatory cell infiltration and changes in cytokines; however, mice transplanted with rAdV-green fluorescent protein (GFP)-infected DCs displayed no asthma manifestations. In conclusion, CTLA4Ig-modified DCs exhibited a therapeutic effect on asthma, and CCR7 may guide DC homing. The combination of these two molecules may be a model for precision-guided immunotherapy.
authors.affiliation: Department of Respiratory Medicine, Children's Hospital of Fudan University, Shanghai 201102, China. yanchenscience@hotmail.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Neonatology, Children's Hospital, Chongqing Medical University, Chongqing 404100, China. yongmingwangscience@hotmail.com.
authors.forename: Yongming
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Respiratory Medicine, Children's Hospital, Chongqing Medical University, Chongqing 404100, China. zhoufuscience@hotmail.com.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Fu
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001249:Asthma / Q000628:therapy*; D060908:CTLA-4 Antigen / Q000235:genetics* / Q000378:metabolism; D002465:Cell Movement; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000502:physiology / Q000637:transplantation; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000276:immunology; D007142:Immunoglobulin gamma-Chains / Q000235:genetics / Q000276:immunology; D007167:Immunotherapy; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D054400:Receptors, CCR7 / Q000235:genetics / Q000378:metabolism*
chemical_list: D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C515371:Ccr7 protein, mouse; D007141:Immunoglobulin Fc Fragments; D007142:Immunoglobulin gamma-Chains; D054400:Receptors, CCR7; D015847:Interleukin-4; D007371:Interferon-gamma