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Prepublished online as a Blood First Edition Paper on January 9, 2003; DOI 10.1182/blood-2002-10-3048.
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Blood, 1 May 2003, Vol. 101, No. 9, pp. 3741-3748
TRANSPLANTATION
Ligation of OX40 (CD134) regulates graft-versus-host
disease (GVHD) and graft rejection in allogeneic bone marrow
transplant recipients
Bruce R. Blazar,
Arlene H. Sharpe,
Andy I. Chen,
Angela Panoskaltsis-Mortari,
Christopher Lees,
Hisaya Akiba,
Hideo Yagita,
Nigel Killeen, and
Patricia A. Taylor
From the University of Minnesota Cancer Center and
Department of Pediatrics, Division of Bone Marrow Transplantation,
Minneapolis, MN; Department of Pathology, Brigham and Women's
Hospital, Boston, MA; the Department of Immunology, Juntendo University
School of Medicine, Tokyo, Japan; and the Department of Microbiology
and Immunology, University of California, San Francisco, CA.
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.
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