title: IL-18-independent cytotoxic T lymphocyte activation and IFN-gamma production during experimental acute graft-versus-host disease.
abstract: 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 T(h)1 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.
authors.affiliation: Division of Immunopathology, Institute of Pathology, University of Bern, Murtenstrasse 31, PO Box 62, 3010, Switzerland.
authors.forename: Diana
authors.initials: D
authors.lastname: Arnold
authors.forename: Christoph
authors.initials: C
authors.lastname: Wasem
authors.forename: Pierre
authors.initials: P
authors.lastname: Juillard
authors.forename: Pierre
authors.initials: P
authors.lastname: Graber
authors.forename: Igor
authors.initials: I
authors.lastname: Cima
authors.forename: Corina
authors.initials: C
authors.lastname: Frutschi
authors.forename: Simon
authors.initials: S
authors.lastname: Herren
authors.forename: Sabine
authors.initials: S
authors.lastname: Jakob
authors.forename: Sami
authors.initials: S
authors.lastname: Alouani
authors.forename: Christoph
authors.initials: C
authors.lastname: Mueller
authors.forename: Yolande
authors.initials: Y
authors.lastname: Chvatchko
authors.forename: Thomas
authors.initials: T
authors.lastname: Brunner
mesh_terms: D000818:Animals; D006086:Graft vs Host Disease / Q000097:blood / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000096:biosynthesis / Q000097:blood / Q000494:pharmacology; D020382:Interleukin-18 / Q000494:pharmacology / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D020382:Interleukin-18; D008070:Lipopolysaccharides; D018664:Interleukin-12; D007371:Interferon-gamma