Structural Requirements and Applications of Inhibitory Oligodeoxyribonucleotides

Overview

Journal Immunol Res

Specialty Allergy & Immunology

Date 2007 Oct 6

PMID 17917051

Citations 9

Authors

Robert F Ashman

Petar Lenert

Affiliations

Soon will be listed here.

Abstract

Synthetic oligodeoxyribonucleotides (ODN) bearing certain sequence characteristics mimic bacterial DNA by activating B cells and dendritic cells through Toll-like receptor (TLR) 9, an event that potentiates both humoral and cell-mediated immunity. ODN sharing some of the sequence characteristics of strong stimulatory (ST-) ODN, but substituting GGG for CGTT, competitively inhibit ST-ODN-driven events. An ODN with the same length and base composition as a strong ST-ODN, but lacking both ST- and IN-sequence requirements, has neither ST- nor IN-activity. Whereas, certain sequence changes strongly influence ST-ODN activity in human cells relative to mouse cells and B cells relative to non B cells, the strongest IN-ODN appear to work well in both species and multiple cell types. Converting from the natural phosphodiester backbone to a nuclease-resistant phosphorothioate backbone increases the sensitivity to ST-ODN about 2 logs and to IN-ODN 3 logs, while increasing the impact of critical base changes in ST-ODN and diminishing it in IN-ODN. Examples where IN-ODN have been used in vivo to interrupt autoimmune and other TLR-9-induced inflammatory states are described.

Citing Articles

Endosomal Toll-Like Receptors Mediate Enhancement of Interleukin-17A Production Triggered by Epstein-Barr Virus DNA in Mice.

Shehab M, Sherri N, Hussein H, Salloum N, Rahal E J Virol. 2019; 93(20).

PMID: 31375581 PMC: 6798095. DOI: 10.1128/JVI.00987-19.

Modulating toll-like receptor 7 and 9 responses as therapy for allergy and autoimmunity.

Matesic D, Lenert A, Lenert P Curr Allergy Asthma Rep. 2011; 12(1):8-17.

PMID: 22086297 DOI: 10.1007/s11882-011-0233-4.

Optimal oligonucleotide sequences for TLR9 inhibitory activity in human cells: lack of correlation with TLR9 binding.

Ashman R, Adam Goeken J, Latz E, Lenert P Int Immunol. 2011; 23(3):203-14.

PMID: 21393636 PMC: 3053407. DOI: 10.1093/intimm/dxq473.

Aggregation and secondary loop structure of oligonucleotides do not determine their ability to inhibit TLR9.

Ashman R, Adam Goeken J, Lenert P Int Immunopharmacol. 2011; 11(8):1032-7.

PMID: 21376154 PMC: 3119753. DOI: 10.1016/j.intimp.2011.02.023.

IFN-α production by human mononuclear cells infected with varicella-zoster virus through TLR9-dependent and -independent pathways.

Yu H, Huang H, Kuo H, Sheen J, Ou C, Hsu T Cell Mol Immunol. 2011; 8(2):181-8.

PMID: 21317915 PMC: 4003143. DOI: 10.1038/cmi.2010.84.

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