Abstract
OX40 (CD134) is expressed on activated T cells; its ligand, OX40 ligand (OX40L) is expressed on dendritic cells, B cells, and activated endothelial cells. To determine how OX40-OX40L interaction affects graft-versus-host disease (GVHD), we used antagonistic anti-OX40L monoclonal antibody (mAb) or OX40(-/-) donor or OX40L(-/-) recipient mice. Similar degrees of GVHD reduction were observed with each approach. Despite the fact that OX40 is up-regulated on both CD4(+) and CD8(+) T cells isolated during GVHD, the major effects of OX40 ligation were on CD4(+) and not CD8(+) T-cell-mediated alloresponses as assessed in both GVHD and engraftment model systems. GVHD inhibition by blockade of the OX40/OX40L pathway did not require CD28 signaling. Some studies have indicated OX40 is essential for inducing T-helper type 2 (Th2) responses. However, in vivo blockade of OX40-OX40L interactions reduced GVHD mortality induced by either signal transducer and activator of transcription-6(-/-) (Stat-6(-/-)) (Th2-defective) or Stat-4(-/-) (Th1-defective) major histocompatibility complex (MHC)-disparate splenocytes, indicating that the GVHD-ameliorating effects did not require Stat-4 or Stat-6 signaling. Although OX40L has been reported to be expressed on activated T cells, no effects on GVHD were observed when OX40L(-/-) versus OX40L(+/+) T cells were infused in different models. These data provide insights as to the mechanisms responsible for OX40/OX40L regulation of GVHD.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antibodies, Monoclonal / immunology
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Antibodies, Monoclonal / pharmacology
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Antibody Specificity
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Bone Marrow Transplantation*
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CD28 Antigens / physiology
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / transplantation
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / transplantation
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Crosses, Genetic
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology
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Dendritic Cells / immunology
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Graft Rejection / immunology*
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Graft vs Host Disease / immunology*
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Graft vs Host Disease / prevention & control
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Membrane Glycoproteins / immunology*
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, SCID
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OX40 Ligand
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Radiation Chimera
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Receptors, OX40
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Receptors, Tumor Necrosis Factor*
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STAT4 Transcription Factor
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STAT6 Transcription Factor
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Signal Transduction
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Specific Pathogen-Free Organisms
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Th1 Cells / immunology
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Th2 Cells / immunology
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Trans-Activators / deficiency
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Trans-Activators / genetics
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Trans-Activators / physiology
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Transplantation, Homologous / immunology*
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Tumor Necrosis Factor Receptor Superfamily, Member 7 / immunology*
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Tumor Necrosis Factors
Substances
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Antibodies, Monoclonal
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CD28 Antigens
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DNA-Binding Proteins
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Membrane Glycoproteins
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OX40 Ligand
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Receptors, OX40
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Receptors, Tumor Necrosis Factor
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STAT4 Transcription Factor
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STAT6 Transcription Factor
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Stat4 protein, mouse
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Stat6 protein, mouse
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Tnfrsf4 protein, mouse
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Tnfsf4 protein, mouse
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Trans-Activators
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Tumor Necrosis Factor Receptor Superfamily, Member 7
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Tumor Necrosis Factors