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Departments of
*
Surgery,
Medicine,
§
Pathology, and
¶
Medical Microbiology and Immunology, Arthur G. James Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210;
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Institute for Medicine, Microbiology, and Hygiene, Munich, Germany;
#
Genetics Institute, Andover, MA 01810;
**
Children’s Hospital, Columbus, OH 43205;
Lineberger Comprehensive Cancer Center, Curriculum in Genetics and Molecular Biology, Chapel Hill, NC 27514;
*
Immunex Research and Development Corporation, Seattle, WA 98101;
*
Vertex Pharmaceuticals, Cambridge, MA 02139; and
*
Roswell Park Cancer Institute, Buffalo, NY 14263
The 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-
, IFN-
,
macrophage-inflammatory protein-1, 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.
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