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CpG oligonucleotides induce acute murine thrombocytopenia dependent on toll-like receptor 9 and spleen tyrosine kinase pathways

Johansson, Karl LU ; Maouia, Amal LU ; Rebetz, Johan LU orcid ; Marcoux, Geneviève LU ; Shannon, Oonagh LU ; Italiano, Joseph E. ; Narayanan, Padma ; Henry, Scott ; Shen, Lijiang and Semple, John W. LU (2024) In Journal of Thrombosis and Haemostasis 22(11). p.3266-3276
Abstract

Background: CpG oligonucleotides (ODNs) are synthetic single-stranded DNA sequences that act as immunostimulants. They have been increasingly used to treat several cancers; however, thrombocytopenia is a potential recognized side effect of some sequences. Objectives: We tested the ability of 2 CpG ODNs (ODN 2395 and ISIS 120704) to induce thrombocytopenia when administered to BALB/c mice and determined mechanisms associated with thrombocytopenia. Methods: BALB/c mice were prebled and then injected with titrated doses of CpG ODNs, and platelet counts were determined. The mice were treated with intravenous immunoglobulin (IVIg) or various inhibitors and antagonists of toll-like receptor 9 (TLR9) and spleen tyrosine kinase (Syk) to... (More)

Background: CpG oligonucleotides (ODNs) are synthetic single-stranded DNA sequences that act as immunostimulants. They have been increasingly used to treat several cancers; however, thrombocytopenia is a potential recognized side effect of some sequences. Objectives: We tested the ability of 2 CpG ODNs (ODN 2395 and ISIS 120704) to induce thrombocytopenia when administered to BALB/c mice and determined mechanisms associated with thrombocytopenia. Methods: BALB/c mice were prebled and then injected with titrated doses of CpG ODNs, and platelet counts were determined. The mice were treated with intravenous immunoglobulin (IVIg) or various inhibitors and antagonists of toll-like receptor 9 (TLR9) and spleen tyrosine kinase (Syk) to determine their effects on thrombocytopenia. Results: Compared with saline-treated mice or mice treated with 2′-O-methoxyethyl–modified antisense ODN, both ODN 2395 and ISIS 120704 induced acute dose-dependent thrombocytopenia within 3 and 24 hours, respectively. The thrombocytopenia was associated with significant increases in plasma monocyte chemoattractant protein 1. IVIg administration significantly rescued the CpG ODN–induced thrombocytopenia, as did treatment with either a Syk inhibitor or TLR9 antagonists. In vitro, CpG ODN could activate human platelets and this correlated significantly with enhanced IVIg- and Syk-dependent phagocytosis by THP-1 monocytes. Conclusion: These results suggest that CpG ODNs induce acute inflammatory-associated (IVIg-sensitive) thrombocytopenia that can be alleviated by Syk- or TLR9-blockade, and an IVIg- and Syk-dependent platelet clearance pathway appears primarily responsible for the thrombocytopenia.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
oligonucleotides, platelet activation/phagocytosis, protein-tyrosine kinase (Syk) inhibition, thrombocytopenia, toll-like receptor (TLR) inhibition
in
Journal of Thrombosis and Haemostasis
volume
22
issue
11
pages
11 pages
publisher
Elsevier
external identifiers
  • pmid:39155024
  • scopus:85203139989
ISSN
1538-7933
DOI
10.1016/j.jtha.2024.08.003
language
English
LU publication?
yes
id
8e935653-af5a-4d11-8e30-bfdd376b690d
date added to LUP
2024-12-13 13:04:43
date last changed
2025-07-12 06:12:22
@article{8e935653-af5a-4d11-8e30-bfdd376b690d,
  abstract     = {{<p>Background: CpG oligonucleotides (ODNs) are synthetic single-stranded DNA sequences that act as immunostimulants. They have been increasingly used to treat several cancers; however, thrombocytopenia is a potential recognized side effect of some sequences. Objectives: We tested the ability of 2 CpG ODNs (ODN 2395 and ISIS 120704) to induce thrombocytopenia when administered to BALB/c mice and determined mechanisms associated with thrombocytopenia. Methods: BALB/c mice were prebled and then injected with titrated doses of CpG ODNs, and platelet counts were determined. The mice were treated with intravenous immunoglobulin (IVIg) or various inhibitors and antagonists of toll-like receptor 9 (TLR9) and spleen tyrosine kinase (Syk) to determine their effects on thrombocytopenia. Results: Compared with saline-treated mice or mice treated with 2′-O-methoxyethyl–modified antisense ODN, both ODN 2395 and ISIS 120704 induced acute dose-dependent thrombocytopenia within 3 and 24 hours, respectively. The thrombocytopenia was associated with significant increases in plasma monocyte chemoattractant protein 1. IVIg administration significantly rescued the CpG ODN–induced thrombocytopenia, as did treatment with either a Syk inhibitor or TLR9 antagonists. In vitro, CpG ODN could activate human platelets and this correlated significantly with enhanced IVIg- and Syk-dependent phagocytosis by THP-1 monocytes. Conclusion: These results suggest that CpG ODNs induce acute inflammatory-associated (IVIg-sensitive) thrombocytopenia that can be alleviated by Syk- or TLR9-blockade, and an IVIg- and Syk-dependent platelet clearance pathway appears primarily responsible for the thrombocytopenia.</p>}},
  author       = {{Johansson, Karl and Maouia, Amal and Rebetz, Johan and Marcoux, Geneviève and Shannon, Oonagh and Italiano, Joseph E. and Narayanan, Padma and Henry, Scott and Shen, Lijiang and Semple, John W.}},
  issn         = {{1538-7933}},
  keywords     = {{oligonucleotides; platelet activation/phagocytosis; protein-tyrosine kinase (Syk) inhibition; thrombocytopenia; toll-like receptor (TLR) inhibition}},
  language     = {{eng}},
  number       = {{11}},
  pages        = {{3266--3276}},
  publisher    = {{Elsevier}},
  series       = {{Journal of Thrombosis and Haemostasis}},
  title        = {{CpG oligonucleotides induce acute murine thrombocytopenia dependent on toll-like receptor 9 and spleen tyrosine kinase pathways}},
  url          = {{http://dx.doi.org/10.1016/j.jtha.2024.08.003}},
  doi          = {{10.1016/j.jtha.2024.08.003}},
  volume       = {{22}},
  year         = {{2024}},
}