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

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 graf t-versus-host disease (GVHD). We investigated the role of IL-18 in this dis order using a well characterized murine bone marrow transplantation (BMT) m odel (B6 --> B6D2F1). Surprisingly, blockade of IL-18 accelerated acute GVH D-related mortality. In contrast, administration of IL-18 reduced serum tum or necrosis factor (TNF)-alpha and lipopolysaccharide (LPS) levels, decreas ed intestinal histopathology, and resulted in significantly improved surviv al (75 vs. 15%, P < 0.001). Administration of IL-18 attenuated early donor T cell expansion and was associated with increased Fas expression and great er apoptosis of donor T cells. The administration of IL-18 no longer protec ted BMT recipients from GVHD when Fas deficient (lpr) mice were used as don ors. IL-18 also lost its ability to protect against acute GVHD when interfe ron (IFN)-gamma knockout mice were used as donors. Together, these results demonstrate that IL-18 regulates acute GVHD by inducing enhanced Fas-mediat ed apoptosis of donor T cells early after BMT, and donor IFN-gamma is criti cal for this protective effect.