The counter regulatory response induced by CpG oligonucleotides prevents bleomycin induced pneumopathy.
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.
Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702, USA.
Takeshi
T
Kinjo
Koji
K
Tomaru
Diana C
DC
Haines
Dennis M
DM
Klinman
D000818:Animals; D001761:Bleomycin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000075202:Contraindications; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000627:therapeutic use*; D011014:Pneumonia / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*
C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; D001761:Bleomycin