The counter regulatory response induced by CpG oligonucleotides prevents bleomycin induced pneumopathy
<p>Abstract</p> <p>Bleomycin (BLM) induces life-threatening pneumonitis and pulmonary fibrosis in 20% of patients, limiting its use as a chemotherapeutic agent. Oligonucleotides expressing immunostimulatory CpG motifs (CpG ODN) stimulate cells that express Toll-like receptor 9 to i...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2012-06-01
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| Series: | Respiratory Research |
| Subjects: | |
| Online Access: | http://respiratory-research.com/content/13/1/47 |
| _version_ | 1818565161276932096 |
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| author | Kinjo Takeshi Tomaru Koji Haines Diana C Klinman Dennis M |
| author_facet | Kinjo Takeshi Tomaru Koji Haines Diana C Klinman Dennis M |
| author_sort | Kinjo Takeshi |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Bleomycin (BLM) induces life-threatening pneumonitis and pulmonary fibrosis in 20% of patients, limiting its use as a chemotherapeutic agent. Oligonucleotides expressing immunostimulatory CpG motifs (CpG ODN) stimulate cells that express Toll-like receptor 9 to initiate an inflammatory response. This short-lived inflammation is physiologically suppressed by a counter-regulatory process that peaks five days later. Using a murine model of BLM-induced lung injury, the effect of CpG ODN treatment on pulmonary inflammation, fibrosis and mortality was examined. Administering CpG ODN 5 days before BLM (so that the peak of the counter-regulatory process induced by CpG ODN coincided with BLM delivery) resulted in a dose-dependent reduction in pulmonary toxicity (p < 0.005). Delaying the initiation of therapy until the day of or after BLM administration worsened the inflammatory process, consistent with the counter-regulatory process rather than initial pro-inflammatory response being critical to CpG induced protection. The protection afforded by CpG ODN correlated with reduced leukocyte accumulation and inflammatory cytokine/chemokine production in the lungs. These changes were associated with the increased production of IL-10, a critical element of the counter-regulatory process triggered by CpG ODN, and the concomitant down-regulation of BLM-induced IL-17A and TGF-β1 (which promote pulmonary toxicity). This work represents the first example of the physiologic counter-regulation of TLR induced immune activation being harnessed to block an unrelated inflammatory response.</p> |
| first_indexed | 2024-12-14T01:37:41Z |
| format | Article |
| id | doaj.art-76a1348a57e646deb5c067004564333a |
| institution | Directory Open Access Journal |
| issn | 1465-9921 |
| language | English |
| last_indexed | 2024-12-14T01:37:41Z |
| publishDate | 2012-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Respiratory Research |
| spelling | doaj.art-76a1348a57e646deb5c067004564333a2022-12-21T23:21:51ZengBMCRespiratory Research1465-99212012-06-011314710.1186/1465-9921-13-47The counter regulatory response induced by CpG oligonucleotides prevents bleomycin induced pneumopathyKinjo TakeshiTomaru KojiHaines Diana CKlinman Dennis M<p>Abstract</p> <p>Bleomycin (BLM) induces life-threatening pneumonitis and pulmonary fibrosis in 20% of patients, limiting its use as a chemotherapeutic agent. Oligonucleotides expressing immunostimulatory CpG motifs (CpG ODN) stimulate cells that express Toll-like receptor 9 to initiate an inflammatory response. This short-lived inflammation is physiologically suppressed by a counter-regulatory process that peaks five days later. Using a murine model of BLM-induced lung injury, the effect of CpG ODN treatment on pulmonary inflammation, fibrosis and mortality was examined. Administering CpG ODN 5 days before BLM (so that the peak of the counter-regulatory process induced by CpG ODN coincided with BLM delivery) resulted in a dose-dependent reduction in pulmonary toxicity (p < 0.005). Delaying the initiation of therapy until the day of or after BLM administration worsened the inflammatory process, consistent with the counter-regulatory process rather than initial pro-inflammatory response being critical to CpG induced protection. The protection afforded by CpG ODN correlated with reduced leukocyte accumulation and inflammatory cytokine/chemokine production in the lungs. These changes were associated with the increased production of IL-10, a critical element of the counter-regulatory process triggered by CpG ODN, and the concomitant down-regulation of BLM-induced IL-17A and TGF-β1 (which promote pulmonary toxicity). This work represents the first example of the physiologic counter-regulation of TLR induced immune activation being harnessed to block an unrelated inflammatory response.</p>http://respiratory-research.com/content/13/1/47BleomycinPneumonitisFibrosisCpG oligonucleotide |
| spellingShingle | Kinjo Takeshi Tomaru Koji Haines Diana C Klinman Dennis M The counter regulatory response induced by CpG oligonucleotides prevents bleomycin induced pneumopathy Respiratory Research Bleomycin Pneumonitis Fibrosis CpG oligonucleotide |
| title | The counter regulatory response induced by CpG oligonucleotides prevents bleomycin induced pneumopathy |
| title_full | The counter regulatory response induced by CpG oligonucleotides prevents bleomycin induced pneumopathy |
| title_fullStr | The counter regulatory response induced by CpG oligonucleotides prevents bleomycin induced pneumopathy |
| title_full_unstemmed | The counter regulatory response induced by CpG oligonucleotides prevents bleomycin induced pneumopathy |
| title_short | The counter regulatory response induced by CpG oligonucleotides prevents bleomycin induced pneumopathy |
| title_sort | counter regulatory response induced by cpg oligonucleotides prevents bleomycin induced pneumopathy |
| topic | Bleomycin Pneumonitis Fibrosis CpG oligonucleotide |
| url | http://respiratory-research.com/content/13/1/47 |
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