In vivo efficacy of a phosphodiester TLR-9 aptamer and its beneficial effect in a pulmonary anthrax infection model

被引:18
作者
Wu, Christina C. N. [1 ]
Sabet, Mojgan [2 ]
Hayashi, Tomoko [1 ]
Tawatao, Rommel [1 ]
Fierer, Joshua [2 ,3 ]
Carson, Dennis A. [1 ]
Guiney, Donald G. [2 ]
Corr, Maripat [4 ]
机构
[1] Univ Calif San Diego, Dept Med, Rebecca & John Moores UCSD Canc Ctr, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Dept Med, Div Infect Dis, La Jolla, CA 92093 USA
[3] VA San Diego Healthcare, Res Serv, San Diego, CA USA
[4] Univ Calif San Diego, Dept Med, Div Rheumatol Allergy & Immunol, La Jolla, CA 92093 USA
关键词
phosphodiester oligonucleotide; TLR-9; cytokines; lung; anthrax;
D O I
10.1016/j.cellimm.2008.04.001
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Immunostimulatory oligonucleotide (ISS-ODN) used as adjuvants are commonly modified with phosphorothioate (PS). The PS backbone prevents nuclease degradation, but confers undesired side effects, including systemic cytokine release. Previously, R10-60, a phosphodiester (PO) ISS-ODN, was structurally optimized as an intracellular Toll-like receptor-9 agonist. Here intravenous, intradermal and intranasal administration of PO R10-60 elicit local or adaptive immune responses with minimal systemic effects compared to a prototypic PS ISS-ODN in mice. Furthermore, prophylactic intranasal administration of PO R10-60 significantly delayed death in mice exposed to respiratory anthrax comparable to the PS ISS-ODN. The pattern of cytokine release suggested that early IL-1 beta production might contribute to this protective effect, which was replicated with recombinant IL-1 beta injections during infection. Hence, the transient effects from a PO TLR-9 agonist may be beneficial for protection in a bacterial bioterrorism attack, by delaying the onset of systemic infection without the induction of a cytokine syndrome. (C) 2008 Elsevier Inc. All rights reserved.
引用
收藏
页码:78 / 85
页数:8
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