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 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.
Reddy
P
P
Department of Internal Medicine and Pediatrics, University of Michigan Cancer Center, 1500 E. Medical Center Dr., Ann Arbor, MI 48109, USA.
Teshima
T
T
Kukuruga
M
M
Ordemann
R
R
Liu
C
C
Lowler
K
K
Ferrara
J L
JL
D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects*; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control*; D007371:Interferon-gamma / Q000502:physiology; D020382:Interleukin-18 / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000502:physiology*; D019014:fas Receptor / Q000502:physiology*
D000911:Antibodies, Monoclonal; D020382:Interleukin-18; D019014:fas Receptor; D007371:Interferon-gamma