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Blood, 15 November 2004, Vol. 104, No. 10, pp. 3393-3399.
Prepublished online as a Blood First Edition Paper on July 27, 2004; DOI 10.1182/blood-2004-02-0763.
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Submitted March 5, 2004
Accepted June 29, 2004
Paradoxical effects of interleukin-18 on the severity of acute graft-versus-host disease mediated by CD4+ and CD8+ T cell subsets after experimental allogeneic bone marrow transplantation
Chang-Ki Min, Yoshinobu Maeda, Kathleen Lowler, Chen Liu, Shawn Clouthier, David Lofthus, Elizabeth Weisiger, James L Ferrara, and Pavan Reddy*
Department of Internal Medicine, University of Michigan Cancer Center, Ann Arbor, MI, USA
Department of Pathology, University of Florida College of Medicine, Gainesville, FL, USA
* Corresponding author; email: reddypr{at}umich.edu.
Abstract
Administration of interleukin-18 (IL-18) regulates experimental acute graft-versus-host disease (GVHD) in a Fas dependent manner when donor CD4+ T cells are required for mortality after experimental allogeneic bone marrow transplantation (BMT). However both CD4+ and CD8+ T cells induce acute GVHD after clinical allogeneic BMT, and the role of IL-18 in CD8+ mediated acute GVHD is not known. We therefore determined the role of IL-18 in GVHD mediated by either CD4+ or CD8+ T cells across MHC class II- and class I-disparate allogeneic BMT respectively. Administration of IL-18 increased survival (25% vs. 0%, P < 0.0001) in CD4+ mediated (class II-disparate) GVHD but surprisingly had the opposite effect in a CD8+ mediated (class I-mismatched) GVHD and dramatically reduced survival (0% vs. 55%, P < 0.0001). This increase in mortality was associated with significantly greater clinical, biochemical and histopathologic parameters of GVHD damage and was independent of Fas expression on donor T cells. Administration of IL-18 significantly enhanced allo-specific cytotoxic function and expansion of CD8+ cells. Endogenous IL-18 was critical to GVHD mediated by CD8+ donor T cells because IL-18 receptor deficient donors caused significantly less GVHD but exacerbated CD4+ mediated GVHD mortality. Furthermore administration of anti-IL-18 monoclonal antibody (mAb) significantly reduced CD8+ mediated GVHD mortality. Together these findings demonstrate that IL-18 has paradoxical effects on CD4+ and CD8+ T cell mediated experimental GVHD.
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