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J. Exp. Med., Volume 188, Number 12, December 21, 1998 2343-2348

The c-kit Ligand, Stem Cell Factor, Can Enhance Innate Immunity Through Effects on Mast Cells

By Marcus Maurer,* Bernd Echtenacher,Dagger Lothar Hültner,§ George Kollias,parallel Daniela N. Männel,Dagger Keith E. Langley, and Stephen J. Galli*

From the * Departments of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215; the Dagger  Institut für Pathologie/Tumorimmunologie, Universität Regensburg, D-93042, Regensburg, Germany; § Forschungszentrum für Umwelt und Gesundheit-Institut für Experimentelle Hämatologie, D-81337, München, Germany; the parallel  Department of Molecular Genetics, Hellenic Pasteur Institute, 115 21 Athens, Greece; and  Amgen Inc., Thousand Oaks, California 91320

Mast cells are thought to contribute significantly to the pathology and mortality associated with anaphylaxis and other allergic disorders. However, studies using genetically mast cell-deficient WBB6F1-KitW/KitW-v and congenic wild-type (WBB6F1-+/+) mice indicate that mast cells can also promote health, by participating in natural immune responses to bacterial infection. We previously reported that repetitive administration of the c-kit ligand, stem cell factor (SCF), can increase mast cell numbers in normal mice in vivo. In vitro studies have indicated that SCF can also modulate mast cell effector function. We now report that treatment with SCF can significantly improve the survival of normal C57BL/6 mice in a model of acute bacterial peritonitis, cecal ligation and puncture (CLP). Experiments in mast cell-reconstituted WBB6F1-KitW/KitW-v mice indicate that this effect of SCF treatment reflects, at least in part, the actions of SCF on mast cells. Repetitive administration of SCF also can enhance survival in mice that genetically lack tumor necrosis factor (TNF)-alpha , demonstrating that the ability of SCF treatment to improve survival after CLP does not solely reflect effects of SCF on mast cell- dependent (or -independent) production of TNF-alpha . These findings identify c-kit and mast cells as potential therapeutic targets for enhancing innate immune responses.

Key words: c-kit;  innate immunity;  mast cells;  stem cell factor;  tumor necrosis factor-alpha


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