The counter regulatory response induced by CpG oligonucleotides prevents bleomycin induced pneumopathy

Respiratory Research

Dennis M Klinman¹  Diana C Haines²  Koji Tomaru¹  Takeshi Kinjo¹ 

[1] Cancer and Inflammation Program, National Cancer Institute, Bldg 567, Rm 205, NCI at Frederick, Frederick, MD, 21702, USA;Pathology and Histotechnology Laboratory, SAIC-Frederick, Inc. National Cancer Institute, Frederick, MD, 21702, USA

关键词: CpG oligonucleotide;    Fibrosis;    Pneumonitis;    Bleomycin;   

Others  :  796714
DOI  :  10.1186/1465-9921-13-47

 received in 2012-02-10, accepted in 2012-06-18,  发布年份 2012

【 摘 要 】

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.

【 授权许可】

   
2012 Kinjo et al.; licensee BioMed Central Ltd.

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