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 M Ferrara, Pavan Reddy

Research output: Contribution to journalArticle

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Abstract

Administration of exogenous 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, CD4+ and CD8+ T cells can induce acute GVHD after clinical allogeneic BMT, and the role of IL-18 in CD8+-mediated acute GVHD is unknown. We, therefore, determined the role of IL-18 in GVHD mediated by CD4+ or CD8 + T cells across major histocompatibility complex (MHC) class II- and class I-disparate allogeneic BMT, respectively. Administering IL-18 significantly increased survival in CD4+-mediated GVHD but reduced survival in CD8+-mediated GVHD. This increase in deaths was associated with significantly greater clinical, biochemical, and histopathologic parameters of GVHD damage and was independent of Fas expression on donor T cells. Administering IL-18 significantly enhanced allospecific 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-related death. Furthermore, administering anti-IL-18 monoclonal antibody significantly reduced CD8+-mediated, GVHD-related death. Together these findings demonstrate that IL-18 has paradoxical effects on CD4+ and CD8+ cell-mediated GVHD.

Original languageEnglish
Pages (from-to)3393-3399
Number of pages7
JournalBlood
Volume104
Issue number10
DOIs
Publication statusPublished - Nov 15 2004
Externally publishedYes

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Interleukin-18
T-cells
Homologous Transplantation
T-Lymphocyte Subsets
Graft vs Host Disease
Bone Marrow Transplantation
Grafts
Bone
T-Lymphocytes
Interleukin-18 Receptors
Major Histocompatibility Complex
Monoclonal Antibodies

ASJC Scopus subject areas

  • Hematology

Cite this

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. / Min, Chang Ki; Maeda, Yoshinobu; Lowler, Kathleen; Liu, Chen; Clouthier, Shawn; Lofthus, David; Weisiger, Elizabeth; Ferrara, James L M; Reddy, Pavan.

In: Blood, Vol. 104, No. 10, 15.11.2004, p. 3393-3399.

Research output: Contribution to journalArticle

Min, Chang Ki ; Maeda, Yoshinobu ; Lowler, Kathleen ; Liu, Chen ; Clouthier, Shawn ; Lofthus, David ; Weisiger, Elizabeth ; Ferrara, James L M ; Reddy, Pavan. / 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. In: Blood. 2004 ; Vol. 104, No. 10. pp. 3393-3399.
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abstract = "Administration of exogenous 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, CD4+ and CD8+ T cells can induce acute GVHD after clinical allogeneic BMT, and the role of IL-18 in CD8+-mediated acute GVHD is unknown. We, therefore, determined the role of IL-18 in GVHD mediated by CD4+ or CD8 + T cells across major histocompatibility complex (MHC) class II- and class I-disparate allogeneic BMT, respectively. Administering IL-18 significantly increased survival in CD4+-mediated GVHD but reduced survival in CD8+-mediated GVHD. This increase in deaths was associated with significantly greater clinical, biochemical, and histopathologic parameters of GVHD damage and was independent of Fas expression on donor T cells. Administering IL-18 significantly enhanced allospecific 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-related death. Furthermore, administering anti-IL-18 monoclonal antibody significantly reduced CD8+-mediated, GVHD-related death. Together these findings demonstrate that IL-18 has paradoxical effects on CD4+ and CD8+ cell-mediated GVHD.",
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