IL-18-independent cytotoxic T lymphocyte activation and IFNγ 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 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‐γ 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‐γ production. We conclude that IL‐18 expression correlates with the course of GvHD; however, its effect is dispensable for IFN‐γ and CTL induction for the initiation phase of this disease, most likely due to direct, IL‐18‐independent, CTL activation.