IL‐18‐independent cytotoxic T lymphocyte activation and IFN‐γ production during experimental acute graft‐versus‐host disease
Acute graft-versus-host disease (GvHD) is a serious complication after allogeneic bone marrow transplantation. Donor-derived T cells in®ltrate 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-in¯ammatory cytokine with potent T h 1 immune response-promoting and cytotoxic T lymphocyte (CTL)-inducing activity. IL-18 is
... tivity. 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 speci®cally 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-g production and CTL induction upon activation by T cell mitogens or by alloantigen does not involve IL-18mediated ampli®cation, in contrast to lipopolysaccharide-induced IFN-g production. We conclude that IL-18 expression correlates with the course of GvHD; however, its effect is dispensable for IFN-g and CTL induction for the initiation phase of this disease, most likely due to direct, IL-18independent, CTL activation.