Immune Responses against Replication-Deficient Adenovirus Inhibit Ovalbumin-Specific Allergic Reactions in Mice

Abstract

Replication-deficient adenovirus vector (Ad) is one of the most efficient gene transfer vehicles for human gene therapy. However, Ad is antigenic, known to evoke prominent inflammatory responses in vivo, and there are concerns that using Ad in patients with immune-mediated disorders (allergy and autoimmune diseases) may affect the status of the diseases. To evaluate this concept in a manner close to clinical scenarios, a mouse model of airway eosinophilic inflammation was developed by administering intraperitoneal injections and inhalations of chicken ovalbumin (OA), with Ad administered intranasally 5 days after the OA sensitization. The administration of Ad resulted in a significant suppression of eosinophil counts in peripheral blood as well as in the bronchoalveolar lavage fluid (BALF), and a decrease in OA-specific IgE. The decrease in the number of eosinophils in BALF was associated with a marked upregulation of interferon gamma (IFN-gamma) expression. In contrast, the Ad-specific, delayed-type hypersensitivity response and efficacy of reporter gene expression mediated by Ad were only marginally affected in animals sensitized with OA. Together, these data support the idea that Ad administration in patients with Th2-mediated immune disorders does not exacerbate the parameters of ongoing inflammations or gene transfer efficiency, and with its ability to induce prominent type 1 immune response to the antigen in vivo, Ad could potentially be used as an efficient adjuvant to control immune disorders where Th2 cell-mediated mechanisms are involved.

Adenovirus expressing Fas ligand gene decreases airway hyper-responsiveness and eosinophilia in a murine model of asthma

“…[25][26][27]43 It has been demonstrated that replicationdefective adenovirus without transgene could inhibit eosinophilic inflammation in the airway of OVA-sensitized mice. 25,44 Furthermore, administration of adenovirus expressing Th1-related cytokines (such as IL-12, IL-18 and IFN-g) reduced AHR and lung inflammation. 26,27 As another strategy in addition to Th1/Th2 modulation, we demonstrated that administration of AdFasL to OVA-sensitized mice reduced AHR and lung eosinophilia.…”

“…[25][26][27] Previous studies have shown that administrations of adenovirusmediated IL-12, IL-18, or IFN-g attenuate established allergen-induced airway inflammation and AHR. 26,27 Furthermore, introduction of this nonreplicanting adenovirus into murine lungs does not induce an inflammatory response in the lungs.…”

Adenoviral vector–mediated gene transfer of IL‐13Rα2 chain followed by IL‐13 cytotoxin treatment offers potent targeted therapy for cytotoxin‐resistant cancers

“…47 The human IL-13R 2 chain cDNA fragment was inserted into the NotI site of shuttle plasmid pCMV-SV2þ, 48 which contains a portion of the adenovirus type 5 (Ad5) genome and the CMV early promoter/enhancer. The shuttle plasmid carrying the expression cassette of IL-13R 2 chain instead of the Ad5 E1 region and adenoviral genomic plasmid pJM17 (Microbix Biosystems, Toronto, Canada) containing the Ad5 genome with E1 and E3 deletions were cotransfected into 293 cells using the CalciumPhosphate Transfection System (Life Technologies, Grand Island, NY).…”

Efficacy of recombinant adenovirus as vector for allergen gene therapy in a mouse model of type I allergy

“…Successful inhibition seems to depend on the immunization protocol used for priming mice. Suzuki et al 41 demonstrated that intranasal instillation of Ad after two sensitizing intraperitoneal injections with OVA lead to decreased IgE Ab production. In contrast, after subsequent aerosol challenge the IgE Ab titers were not significantly different from those of untreated control mice, although profound effects on eosinophil infiltration in the airways and local cytokine production were observed.…”