A Fatal Cytokine-Induced Systemic Inflammatory Response Reveals a Critical Role for NK Cells

Author:

Carson William E.12,Yu Haixin2,Dierksheide Julie3,Pfeffer Klaus4,Bouchard Page5,Clark Reed6,Durbin Joan6,Baldwin Albert S.7,Peschon Jacques8,Johnson Philip R.6,Ku George9,Baumann Heinz10,Caligiuri Michael A.211

Affiliation:

1. *Department of Surgery, Arthur G. James Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210;

2. †Department of Medical Microbiology and Immunology, Arthur G. James Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210;

3. ‡Department of Pathology, Arthur G. James Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210;

4. §Institute for Medicine, Microbiology, and Hygiene, Munich, Germany;

5. ¶Genetics Institute, Andover, MA 01810;

6. ||Children’s Hospital, Columbus, OH 43205;

7. **Lineberger Comprehensive Cancer Center, Curriculum in Genetics and Molecular Biology, Chapel Hill, NC 27514;

8. ††Immunex Research and Development Corporation, Seattle, WA 98101;

9. ‡‡Vertex Pharmaceuticals, Cambridge, MA 02139; and

10. §§Roswell Park Cancer Institute, Buffalo, NY 14263

11. ¶¶Department of Medicine, Arthur G. James Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210;

Abstract

AbstractThe mechanism of cytokine-induced shock remains poorly understood. The combination of IL-2 and IL-12 has synergistic antitumor activity in vivo, yet has been associated with significant toxicity. We examined the effects of IL-2 plus IL-12 in a murine model and found that the daily, simultaneous administration of IL-2 and IL-12 resulted in shock and 100% mortality within 4 to 12 days depending on the strain employed. Mice treated with IL-2 plus IL-12 exhibited NK cell apoptosis, pulmonary edema, degenerative lesions of the gastrointestinal tract, and elevated serum levels of proinflammatory cytokines and acute phase reactants. The actions of TNF-α, IFN-γ, macrophage-inflammatory protein-1α, IL-1, IL-1-converting enzyme, Fas, perforin, inducible nitric oxide synthase, and STAT1 did not contribute to the observed toxicity, nor did B or T cells. However, toxicity and death from treatment with IL-2 plus IL-12 could be completely abrogated by elimination of NK cells. These results suggest that the fatal systemic inflammatory response induced by this cytokine treatment is critically dependent upon NK cells, but does not appear to be mediated by the known effector molecules of this cellular compartment. These data may provide insight into the pathogenesis of cytokine-induced shock in humans.

Publisher

The American Association of Immunologists

Subject

Immunology,Immunology and Allergy

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