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

Pavan Reddy, Takanori Teshima, Mark Kukuruga, Rainer Ordemann, Chen Liu, Kathy Lowler, James L.M. Ferrara

Research output: Contribution to journalArticlepeer-review

148 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1433-1440
Number of pages8
JournalJournal of Experimental Medicine
Volume194
Issue number10
DOIs
StatePublished - Nov 19 2001
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Keywords

  • Bone marrow transplantation
  • IFN-γ
  • LPS
  • TNF-α
  • Th1/Th2 cytokines

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