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CpG-containing immunostimulatory DNA sequences elicit TNF-alpha-dependent toxicity in rodents but not in humans.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2009 Sep; Vol. 119 (9), pp. 2564-76. Date of Electronic Publication: 2009 Aug 10. - Publication Year :
- 2009
-
Abstract
- CpG-containing immunostimulatory DNA sequences (ISS), which signal through TLR9, are being developed as a therapy for allergic indications and have proven to be safe and well tolerated in humans when administrated via the pulmonary route. In contrast, ISS inhalation has unexplained toxicity in rodents, which express TLR9 in monocyte/macrophage lineage cells as well as in plasmacytoid DCs (pDCs) and B cells, the principal TLR9-expressing cells in humans. We therefore investigated the mechanisms underlying this rodent-specific toxicity and its implications for humans. Mice responded to intranasally administered 1018 ISS, a representative B class ISS, with strictly TLR9-dependent toxicity, including lung inflammation and weight loss, that was fully reversible and pDC and B cell independent. Knockout mouse experiments demonstrated that ISS-induced toxicity was critically dependent on TNF-alpha, with IFN-alpha required for TNF-alpha induction. In contrast, human PBMCs, human alveolar macrophages, and airway-derived cells from Ascaris suum-allergic cynomolgus monkeys did not produce appreciable TNF-alpha in vitro in response to ISS stimulation. Moreover, sputum of allergic humans exposed to inhaled ISS demonstrated induction of IFN-inducible genes but minimal TNF-alpha induction. These data demonstrate that ISS induce rodent-specific TNF-alpha-dependent toxicity that is absent in humans and reflective of differential TLR9 expression patterns in rodents versus humans.
- Subjects :
- Adjuvants, Immunologic toxicity
Administration, Inhalation
Animals
Asthma genetics
Asthma immunology
Bronchoalveolar Lavage Fluid immunology
Cytokines metabolism
Dendritic Cells drug effects
Dendritic Cells immunology
Humans
In Vitro Techniques
Lung drug effects
Lung immunology
Lung pathology
Macaca fascicularis
Mice
Mice, Inbred C57BL
Mice, Knockout
Oligodeoxyribonucleotides administration & dosage
Oligodeoxyribonucleotides genetics
Oligodeoxyribonucleotides immunology
Species Specificity
Toll-Like Receptor 9 agonists
Toll-Like Receptor 9 deficiency
Toll-Like Receptor 9 genetics
Toll-Like Receptor 9 metabolism
Tumor Necrosis Factor-alpha deficiency
Tumor Necrosis Factor-alpha genetics
Oligodeoxyribonucleotides toxicity
Tumor Necrosis Factor-alpha metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 119
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 19726873
- Full Text :
- https://doi.org/10.1172/JCI38294