Adenoviral Expression of Suppressor of Cytokine Signaling-1 Reduces Adenovirus Vector-Induced Innate Immune Responses

Abstract

Adenovirus (Ad) vectors are among the most commonly used viral vectors in gene therapy clinical trials. However, the application of Ad vectors has been limited to local injection in many cases, because the systemic administration of Ad vectors triggers innate immune responses such as inflammatory cytokine production and tissue damage. To overcome this limitation, it will be necessary to develop safer Ad vectors less likely to induce the innate immune response. In the present study, we demonstrated that a suppressor of cytokine signaling-1 (SOCS1)-expressing Ad vector, Ad-SOCS1, reduces the innate immune response induced by Ad vectors. RAW264.7-SOCS1, a macrophage-like cell line that stably expresses SOCS1, was shown to produce lower levels of inflammatory cytokines after the transduction of Ad vectors. The systemic administration of Ad-SOCS1 into mice elicited the reduced production of inflammatory cytokines, as compared with that elicited by control Ad vectors, i.e., luciferase-expressing Ad vector, Ad-L2. Furthermore, the coadministration of Ad-L2 with Ad-SOCS1 attenuated inflammatory cytokine production and liver toxicity as compared with injection with Ad-L2 alone, and this was achieved without the suppression of luciferase production in various organs. The JAK/STAT pathway was involved in Ad vector-mediated cytokine production, which was impaired by the overexpression of SOCS1. These findings indicate that Ad-SOCS1 could be useful for reducing Ad vector-mediated innate immunity.

Quality of the Transgene-Specific CD8+ T Cell Response Induced by Adenoviral Vector Immunization Is Critically Influenced by Virus Dose and Route of Vaccination

“…inoculation as it provides an easier accessible and more defined organ site with respect to subsequent quantitation of virus. Consistent with a direct capacity of the adenovirus vector to transduce hepatic cells and splenic macrophages (32)(33)(34), there was a reasonable dose correlation in liver and spleen transduction following i.v. immunization (9.2-and 3.1-fold increases for each 10-fold increase in virus dose in the liver and 5.8-and 11-fold in the spleen).…”

Dendritic Cells Transduced with SOCS1 Gene Exhibit Regulatory DC Properties and Prolong Allograft Survival

“…According to cell type, the adenoviral vector promoted the surface expression of maturation marker molecules in antigen-presenting cells through a Toll-like receptor 9 (TLR-9) dependent or independent manner (39). However, the adenoviral expression of SOCS1 could reduce the immune response of the adenovirus vector itself, due to interference with the JAK-STAT pathway (40). Our experiment results also indicated that DCs induced an increase in CD40, CD80, and Ia expression upon being transfected with Ad-VNG; however, this promotion of maturation effect initiated by the vector itself could be efficiently inhibited when turning to Ad-SOCS1.…”

“…In SOCS1 −/− mouse, the development process of T cells in the thymus was in disorder, and the peripheral T cells exhibited abnormal activation accompanied by Th2 cells in a disturbed state. SOCS1 −/− macrophages produce large amounts of inflammatory cytokines in response to lipopolysaccharide (19), while the macrophages overexpressing SOCS1 can reduce adenovirus vector-induced innate immune responses (20). Recent research revealed that silencing the SOCS1 gene in DCs with the RNA interference technique can contribute to DC maturity and thus increase their antitumor immunity (21).…”

Systemic administration of a PEGylated adenovirus vector with a cancer-specific promoter is effective in a mouse model of metastasis

“…36,37 Macrophages in the liver or spleen efficiently take up Adv; this results in strong activation of the immune response. 38 PEGylation of Adv decreases the innate immune responses, 35,39,40 and PEG[20K/45%]-Ad reduced the innate immune responses after systemic administration (Figure 2c). This reduced innate immune response is likely to be correlated with a reduction in vector uptake by macrophages.…”