Submitted October 18, 2002
Accepted December 23, 2002
Ligation of OX40 (CD134) regulates graft-versus-host disease (GVHD) and graft rejection in allogenic bone marrow transplant (BMT) 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
Department of Pediatrics, Division of Bone Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN, USA
Department of Pathology, Bringham and Women's Hospital, Boston, MA, USA
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan
Department of Microbiology and Immunology, University of California, San Francisco, CA, USA
* Corresponding author; email: blaza001{at}umn.edu.
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 GVHD, we utilized antagonistic anti-OX40L mAbs or OX40-/- donor or OX40L-/- recipient mice. Similar degrees of GVHD reduction were observed with each approach. Despite the fact that OX40 is upregulated 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 Th2 responses. However, in vivo blockade of OX40/OX40L interactions reduced GVHD mortality induced by either Stat-6-/- (Th2-defective) or Stat-4-/- (Th1-defective) 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-/- vs OX40L+/+ T-cells were infused in different models. These data provide insights as to the mechanism(s) responsible for OX40/OX40L regulation of GVHD.
