IL-18 prevents the development of chronic graft-versus-host disease in mice

The development of chronic graft-versus-host disease (GVHD), which is induc ed by the transfer of DBA/2 spleen cells into (C57BL/6 x DBA/2)F-1 (BDF1) m ice, is closely related to diminished donor anti-host CTL activity and host B cell hyperactivation, Therefore, an approach which activates donor CD8() T cells or suppresses donor CD4(+) T cell-host B cell interaction may hav e clinical utility in the treatment of chronic GVHD, We have previously dem onstrated that IL-18 induces the development of naive CD8(+) T cells into t ype I effector cells in DBA/2 anti-BDF1 MLC. In this paper we examined the effect of IL-18 administration on the development of chronic GVHD in mice. The treatment was started before or after the onset of clinical evidence of the disease. ;Regardless of the treatment schedule, IL-18 significantly de creased immunological parameters indicative of chronic GVHD, such as elevat ed serum IgG antinuclear Abs, IgG1, and IgE levels, and host B cell numbers and their activation. Importantly, IL-18-treated mice did not show the sam e acute GVHD-like symptoms reported for IL-12 treatment, because there was no weight loss, death, or severe immunodeficiency as indicated by a decreas e in IL-2 and IFN-gamma production by Con A-stimulated spleen cells. In con trast, IL-18 treatment partially but significantly restored the production of these cytokines. Data further suggested that these IL-18-mediated therap eutic effects may be due to the induction of donor CD8(+) CTL, the decrease in donor CD4+ T cell numbers, and a down-regulation of host B cell MHC cla ss II expression. Thus, our results suggest that IL-18 has beneficial effec ts in the prevention and treatment of chronic GVHD.