Coadministration of interleukin-18 and interleukin-12 induces a fatal inflammatory response in mice:: critical role of natural killer cell interferon-γ production and STAT-mediated signal transduction

被引:97
作者
Carson, WE
Dierksheide, JE
Jabbour, S
Angheina, M
Bouchard, P
Ku, G
Yu, HX
Baumann, H
Shah, MH
Cooper, MA
Durbin, J
Caligiuri, MA
机构
[1] Ohio State Univ, Arthur G James Comprehens Canc Ctr, Dept Pathol, Columbus, OH 43210 USA
[2] Ohio State Univ, Arthur G James Comprehens Canc Ctr, Dept Med, Columbus, OH 43210 USA
[3] Ohio State Univ, Arthur G James Comprehens Canc Ctr, Dept Surg, Columbus, OH 43210 USA
[4] Childrens Hosp, Columbus, OH 43205 USA
[5] Vertex Pharmaceut, Cambridge, MA USA
[6] Genet Inst, Andover, MA USA
[7] Roswell Pk Canc Inst, Buffalo, NY 14263 USA
关键词
D O I
10.1182/blood.V96.4.1465.h8001465_1465_1473
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The administration of therapeutic doses of recombinant cytokines to patients with malignant disease can be complicated by systemic toxicities, which in their most severe form may present as a systemic inflammatory response. The combination of interleukin (IL)-18 and IL-12 has synergistic antitumor activity in vivo yet has been associated with significant toxicity. The effects of IL-18 plus IL-12 were examined in a murine model, and it was found that the daily, simultaneous administration of IL-18 and IL-12 resulted in systemic inflammation and 100% mortality within 4 to 8 days depending on the strain employed. Mice treated with IL-18 plus IL-12 exhibited unique pathologic findings as well as elevated serum levels of proinflammatory cytokines and acute-phase reactants. The actions of tumor necrosis factor-alpha did not contribute to the observed toxicity, nor did T or B cells. However, toxicity and death from treatment with IL-18 plus IL-12 could be completely abrogated by elimination of natural killer (NK) cells or macrophages. Subsequent studies in genetically altered mice revealed that NK-cell interferon-gamma, mediated the fatal toxicity via the signal transducer and activator of transcription pathway of signal transduction. These data may provide insights into methods of ameliorating cytokine-induced shock in humans. (Blood. 2000;96:1465-1473) (C) 2000 by The American Society of Hematology.
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收藏
页码:1465 / 1473
页数:9
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