Abstract: The major limitation of the clinical use of replication-incompetent adenovirus (Ad) vectors is the interference by innate immune responses, including induction of inflammatory cytokines and interferons (IFN), following in vivo application of Ad vectors. Ad vector-induced production of inflammatory cytokines and IFNs also results in severe organ damage and efficient induction of acquired immune responses against Ad proteins and transgene products. Ad vector-induced innate immune responses are triggered by the recognition of Ad components by pattern recognition receptors (PRRs). In order to reduce the side effects by Ad vector-induced innate immune responses and to develop safer Ad vectors, it is crucial to clarify which PRRs and which Ad components are involved in Ad vector-induced innate immune responses. Our group previously demonstrated that myeloid differentiating factor 88 (MyD88) and toll-like receptor 9 (TLR9) play crucial roles in the Ad vector-induced inflammatory cytokine production in mouse bone marrow-derived dendritic cells. Furthermore, our group recently found that virus associated-RNAs (VA-RNAs), which are about 160 nucleotide-long non-coding small RNAs encoded in the Ad genome, are involved in IFN production through the IFN-β promoter stimulator-1 (IPS-1)-mediated signaling pathway following Ad vector transduction. The aim of this review is to highlight the Ad vector-induced innate immune responses following transduction, especially VA-RNA-mediated innate immune responses. Our findings on the mechanism of Ad vector-induced innate immune responses should make an important contribution to the development of safer Ad vectors, such as an Ad vector lacking expression of VA-RNAs.
Keywords: adenovirus vector; VA-RNA; gene therapy; innate immunity
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Machitani, M.; Yamaguchi, T.; Shimizu, K.; Sakurai, F.; Katayama, K.; Kawabata, K.; Mizuguchi, H. Adenovirus Vector-Derived VA-RNA-Mediated Innate Immune Responses. Pharmaceutics 2011, 3, 338-353.
Machitani M, Yamaguchi T, Shimizu K, Sakurai F, Katayama K, Kawabata K, Mizuguchi H. Adenovirus Vector-Derived VA-RNA-Mediated Innate Immune Responses. Pharmaceutics. 2011; 3(3):338-353.
Machitani, Mitsuhiro; Yamaguchi, Tomoko; Shimizu, Kahori; Sakurai, Fuminori; Katayama, Kazufumi; Kawabata, Kenji; Mizuguchi, Hiroyuki. 2011. "Adenovirus Vector-Derived VA-RNA-Mediated Innate Immune Responses." Pharmaceutics 3, no. 3: 338-353.