Structural requirements and applications of inhibitory oligodeoxyribonucleotides
- 83 Downloads
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.
KeywordsInhibitory oligonucleotides TLR9 Stimulatory oligonucleotides Autoimmunity Bacterial DNA
Expert secretarial assistance by Deanna Ollendick, technical assistance by Adam Goeken, and collaboration with Eicke Latz and Douglas Golenbock are gratefully acknowledged. Supported by RO1 AI 47374–04 from the NIH.
- 31.Gursel I, Gursel M, Yamada H, Ishii KJ,Takeshita F, Klinman DM. Repetitive elements in mammalian telomeres suppress bacterial DNA-induced immune activation. J Immunol 2003;117:1393–400.Google Scholar