The CpG motifs of bacterial DMA are among the microbial molecular patterns recognized as """"""""danger signals"""""""" by our innate immune system, requiring Toll-Like Receptor (TLR) 9. Short synthetic oligodeoxyribonucleotides (ODN) have facilitated studies of structure-function relationships. The ability of stimulatory (ST-) ODN to activate B cells, macrophages, and dendritic cells directly, thus triggering humoral and TH1 immunity together, gives them valuable potential roles as vaccine adjuvants and as therapy in cancer and allergy. Changing as few as 2 bases converts a strong ST-ODN into an inhibitor (IN-ODN) that blocks TLR9 but not the other TLRs. With support from the current grant the sequence requirements for IN- ODN action in mouse cells have been defined. Only 3 pairs of positions out of 15 determine IN-ODN activity. The same panel of IN-ODN can block the ST-ODN preferred by B cells (Type B) and non-B cells (Type A). We request continued support in order to address these questions: 1) Do IN-ODN compete with ST-ODN for TLR9 binding? 2) Does the strength of binding of ST-ODN and IN-ODN for TLR9 determine their biologic activity? 3) Do ST-ODN or IN-ODN tie TLR9 molecules together? Does the ability of ODN to aggregate with themselves or each other allow them to do this? 4) Where in the cell does the competition between ST-ODN and IN-ODN take place? 5) Can IN-ODN block ST-ODN activity in vivo? Do the same subtle structural requirements apply? Examples to be used are a model of ODN-induced """"""""septic shock"""""""" and an inflammatory colitis in mice. 6) What are the IN-ODN structural requirements for human cells? Do they differ between ODN types? The answers to these questions are pertinent both to understanding the mechanism of ODN responses and to developing further applications to human disease, especially the prospect of treating lupus and rheumatoid arthritis with IN-ODN.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI047374-07
Application #
7587442
Study Section
Special Emphasis Panel (ZRG1-III (01))
Program Officer
Palker, Thomas J
Project Start
2000-04-01
Project End
2011-02-28
Budget Start
2009-03-01
Budget End
2011-02-28
Support Year
7
Fiscal Year
2009
Total Cost
$321,843
Indirect Cost
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Ashman, Robert F; Goeken, J Adam; Lenert, Petar S (2011) Aggregation and secondary loop structure of oligonucleotides do not determine their ability to inhibit TLR9. Int Immunopharmacol 11:1032-7
Layer, T; Steele, A; Goeken, J A et al. (2011) Engagement of the B cell receptor for antigen differentially affects B cell responses to Toll-like receptor-7 agonists and antagonists in BXSB mice. Clin Exp Immunol 163:392-403
Goeken, J A; Layer, T; Fleenor, S et al. (2010) B-cell receptor for antigen modulates B-cell responses to complex TLR9 agonists and antagonists: implications for systemic lupus erythematosus. Lupus 19:1290-301
Lenert, P (2010) Nucleic acid sensing receptors in systemic lupus erythematosus: development of novel DNA- and/or RNA-like analogues for treating lupus. Clin Exp Immunol 161:208-22
Lenert, Petar S (2010) Classification, mechanisms of action, and therapeutic applications of inhibitory oligonucleotides for Toll-like receptors (TLR) 7 and 9. Mediators Inflamm 2010:986596
Lenert, Petar; Yasuda, Kei; Busconi, Liliana et al. (2009) DNA-like class R inhibitory oligonucleotides (INH-ODNs) preferentially block autoantigen-induced B-cell and dendritic cell activation in vitro and autoantibody production in lupus-prone MRL-Fas(lpr/lpr) mice in vivo. Arthritis Res Ther 11:R79
Ashman, Robert F; Lenert, Petar (2007) Structural requirements and applications of inhibitory oligodeoxyribonucleotides. Immunol Res 39:4-14
Lenert, Petar S (2006) Targeting Toll-like receptor signaling in plasmacytoid dendritic cells and autoreactive B cells as a therapy for lupus. Arthritis Res Ther 8:203
Lenert, Petar; Goeken, Adam J; Ashman, Robert F (2006) Extended sequence preferences for oligodeoxyribonucleotide activity. Immunology 117:474-81
Lenert, P (2005) Inhibitory oligodeoxynucleotides - therapeutic promise for systemic autoimmune diseases? Clin Exp Immunol 140:1-10

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