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International Immunology, Vol. 14, No. 5, pp. 503-511, May 2002
© 2002 Japanese Society for Immunology

IL-18-independent cytotoxic T lymphocyte activation and IFN-{gamma} production during experimental acute graft-versus-host disease

Diana Arnold1, Christoph Wasem1, Pierre Juillard2, Pierre Graber2, Igor Cima1, Corina Frutschi1, Simon Herren1, Sabine Jakob1, Sami Alouani2, Christoph Mueller1, Yolande Chvatchko2 and Thomas Brunner1

1 Division of Immunopathology, Institute of Pathology, University of Bern, Murtenstrasse 31, PO Box 62, 3010 Bern, Switzerland 2 Serono Pharmaceutical Research Institute, Immunology Department, 14 Chemin les Aulx, 1228 Plan-Les-Ouates, Geneva, Switzerland

Correspondence to: T. Brunner; E-mail: tbrunner{at}pathology.unibe.ch
Transmitting editor: A. Falus

Acute graft-versus-host disease (GvHD) is a serious complication after allogeneic bone marrow transplantation. Donor-derived T cells infiltrate recipient target organs and cause severe tissue damage, often leading to death of the affected patient. Tissue destruction is a direct result of donor CD8+ T cell activation and cell-mediated cytotoxicity. IL-18 is a novel pro-inflammatory cytokine with potent Th1 immune response-promoting and cytotoxic T lymphocyte (CTL)-inducing activity. IL-18 is strongly induced in experimental mouse models and human patients with acute GvHD. However, the precise role of IL-18 in the development of acute GvHD is still unknown. In this study, we have used IL-18-binding protein, a soluble IL-18 decoy receptor, to specifically neutralize IL-18 in vivo and in vitro. Our results demonstrate that IL-18 is induced during GvHD. However, its effect in the induction of GvHD appears to be redundant, since neutralization of IL-18 does not alter any disease parameter analyzed. Our study further shows that IFN-{gamma} production and CTL induction upon activation by T cell mitogens or by alloantigen does not involve IL-18-mediated amplification, in contrast to lipopolysaccharide-induced IFN-{gamma} production. We conclude that IL-18 expression correlates with the course of GvHD; however, its effect is dispensable for IFN-{gamma} and CTL induction for the initiation phase of this disease, most likely due to direct, IL-18-independent, CTL activation.

Keywords: cytokines, cytotoxicity, Fas ligand, intestine, intraepithelial lymphocyte, lipopolysaccharide, mixed leukocyte reaction, rodents, T lymphocytes


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