Adenovirus Vector-Derived VA-RNA-Mediated Innate Immune Responses

Pharmaceutics

Mitsuhiro Machitani¹  Tomoko Yamaguchi²  Kahori Shimizu¹  Fuminori Sakurai¹  Kazufumi Katayama¹  Kenji Kawabata² 

[1] Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Yamadaoka, Suita, Osaka, 565-0871, Japan;Laboratory of Stem Cell Regulation, National Institute of Biomedical Innovation (NiBio), Osaka,567-0085, Japan

关键词: adenovirus vector;    VA-RNA;    gene therapy;    innate immunity;   

DOI  :  10.3390/pharmaceutics3030338

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2011 by the authors; licensee MDPI, Basel, Switzerland