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.
Highlights
Human allergic asthma is characterized by airway inflammation, airway hyperresponsiveness and reversible airway intermittent obstruction [1,2,3]
These are summarized as follows: a required but insufficient signal, T-cell receptor (TCR) binding to a specific antigen displayed on the antigen major histocompatibility complex (MHC) delivered by dendritic cells (DCs), and essential signals delivered by co-signaling molecules
To determine the optimal multiplicity of infection (MOI), recombinant adenovirus (rAdV)-GPF, rAdV-chemokine receptor type7 (CCR7) and rAdV-CTLA4 fused with the IgCγ Fc (CTLA4Ig) were titrated by plaque forming assay
Summary
Human allergic asthma is characterized by airway inflammation, airway hyperresponsiveness and reversible airway intermittent obstruction [1,2,3]. The development and activation of T cells require an ordered series of signals from antigen-presenting cells (APCs), such as dendritic cells (DCs) [16,17] These are summarized as follows: a required but insufficient signal, T-cell receptor (TCR) binding to a specific antigen displayed on the antigen major histocompatibility complex (MHC) delivered by DCs, and essential signals delivered by co-signaling molecules. The expression characteristics and the role of CCR7 in DCs are poorly understood, and a limited number of studies showed that after blockade of the CD80/CD86-CD28 axis, CCR7 expression is decreased [32], to optimize CD80/CD86-CD28 axis based immuno-corrective therapy, in this study, we generated a recombinant adenovirus vector harboring the human CTLA4Ig chimeric DNA expression fragment. After modification of the DCs using these viral vectors, the therapeutic effects of CCR7-guided CTLA4Ig were evaluated in a mouse asthma model
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