IL‐18‐independent cytotoxic T lymphocyte activation and IFN‐γ 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.

Paradoxical effects of interleukin-18 on the severity of acute graft-versus-host disease mediated by CD4+ and CD8+ T-cell subsets after experimental allogeneic bone marrow transplantation

“…IL-18 is elevated during acute GVHD, 7,8 but paradoxically it can regulate acute GVHD in a donor/recipient strain Figure 6. IL-18 receptor 1-deficient donor T cells have differential effects on CD4 ؉ -and CD8 ؉ -mediated acute GVHD-related mortality.…”

“…4 Serum levels of IL-18 are elevated in clinical and experimental acute GVHD. 7,8 IL-18 prevents murine chronic GVHD, 9 but its effect on the induction of acute GVHD is unclear. In nonirradiated BMT recipients, neutralizing IL-18 did not alter any acute GVHD parameter analyzed.…”

“…In nonirradiated BMT recipients, neutralizing IL-18 did not alter any acute GVHD parameter analyzed. 8 Recently, however, Reddy et al 10 have demonstrated that administering IL-18 reduces the mortality rate in a lethally irradiated murine BMT model of B6 (H-2 b ) 3 B6D2F1 (H-2 b/d ) acute GVHD induced primarily by CD4 ϩ cells in response to multiple major histocompatibility complex (MHC) and minor histocompatibility antigens. 11 Protection against GVHD in that model depended on the expression of Fas and on enhanced donor T-cell apoptosis.…”

Interleukin-18: recent advances

“…Therefore, caution must be exercised in clinical application of IL-18 after allogeneic BMT. Moreover, Arnold et al [66] used IL-18BP to neutralize IL-18 in a nonirradiated model of acute GVHD and observed no change in GVHD severity. Thus, it is possible that significantly different results might also be obtained in the context of sublethal or nonirradiation.…”

Increased expression of IL-18 in cutaneous graft-versus-host disease

“…Elevated IL-18 expression has been detected in serum and spleen of acute GVHD-affected patients and animals, correlating with the disease progression and the serum IFN-␥ levels [9]. Therefore, IL-18 may play a disease-promoting, proinflammatory role in the onset of acute GVHD [9,[15][16][17][18][19]. However, cutaneous IL-18 expression was inversely correlated by the grading in this study.…”