The Journal of Experimental Medicine
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Published 12 November 2001. doi:10.1084/jem.194.10.1433
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© Rockefeller University Press, 0022-1007/2001/11/1433/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 10, November 19, 2001 1433-1440

Original Article

Interleukin-18 Regulates Acute Graft-Versus-Host Disease by Enhancing Fas-mediated Donor T Cell Apoptosis

Pavan Reddy1, Takanori Teshima1, Mark Kukuruga1, Rainer Ordemann1, Chen Liu2, Kathy Lowler1 and James L.M. Ferrara1

1 Department of Internal Medicine and Pediatrics, University of Michigan Cancer Center, Ann Arbor, MI 48109
2 Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610

Address correspondence to J.L.M. Ferrara, University of Michigan Cancer Center, 1500 E. Medical Center Dr., Ann Arbor, MI 48109. Phone: 734-615-1340; Fax: 734-647-9271; E-mail: ferrara{at}umich.edu

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)-{alpha} 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)-{gamma} 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-{gamma} is critical for this protective effect.

Key Words: bone marrow transplantation • Th1/Th2 cytokines • IFN-{gamma} • LPS • TNF-{alpha}


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