Interleukin-18 regulates acute graft-versus-host disease by enhancing Fas-mediated donor T cell apoptosis

P Reddy, T Teshima, M Kukuruga… - The Journal of …, 2001 - rupress.org
P Reddy, T Teshima, M Kukuruga, R Ordemann, C Liu, K Lowler, JLM Ferrara
The Journal of experimental medicine, 2001rupress.org
Interleukin (IL)-18 is a recently discovered cytokine that modulates both T helper type 1
(Th1) and Th2 responses. IL-18 is elevated during acute graft-versus-host disease (GVHD).
We investigated the role of IL-18 in this disorder using a well characterized murine bone
marrow transplantation (BMT) model (B6→ B6D2F1). Surprisingly, blockade of IL-18
accelerated acute GVHD-related mortality. In contrast, administration of IL-18 reduced serum
tumor necrosis factor (TNF)-α and lipopolysaccharide (LPS) levels, decreased intestinal …
Interleukin (IL)-18 is a recently discovered cytokine that modulates both T helper type 1 (Th1) and Th2 responses. IL-18 is elevated during acute graft-versus-host disease (GVHD). We investigated the role of IL-18 in this disorder using a well characterized murine bone marrow transplantation (BMT) model (B6 → B6D2F1). Surprisingly, blockade of IL-18 accelerated acute GVHD-related mortality. In contrast, administration of IL-18 reduced serum tumor necrosis factor (TNF)-α and lipopolysaccharide (LPS) levels, decreased intestinal histopathology, and resulted in significantly improved survival (75 vs. 15%, P < 0.001). Administration of IL-18 attenuated early donor T cell expansion and was associated with increased Fas expression and greater apoptosis of donor T cells. The administration of IL-18 no longer protected BMT recipients from GVHD when Fas deficient (lpr) mice were used as donors. IL-18 also lost its ability to protect against acute GVHD when interferon (IFN)-γ knockout mice were used as donors. Together, these results demonstrate that IL-18 regulates acute GVHD by inducing enhanced Fas-mediated apoptosis of donor T cells early after BMT, and donor IFN-γ is critical for this protective effect.
rupress.org