Regulation of OX40 gene expression in graft-versus-host disease

OX40 (CD134), a member of the tumor necrosis factor receptor superfamily, is expressed on activated T cells, including CD4(+)CD25(+) T regulatory (Treg) cells. To investigate the kinetics of OX40-OX40L in graft-versus-host disease (GVHD), OX40 mRNA transcript levels were temporally examined in peripheral blood mononuclear cells (PBMCs) from patients undergoing either allogeneic (allo) bone marrow transplantation (alloBMT) or autologous (auto) BMT with the induction of autoGVHD by cyclosporine (CsA) treatment posttransplant. Real-time quantitative PCR analysis revealed that OX40 mRNA expression decreased significantly in PBMCs from patients with either alloGVHD or autoGVHD compared with healthy individuals. No differences were detected between patients developing alloGVHD and those who did not develop this posttransplant complication. On the other hand, a decrease in OX40 mRNA levels correlated directly with the development of autoGVHD. Moreover, the upregulation of OX40 gene expression coincided with the resolution of autoGVHD. Interestingly, expression of OX40 by CD4(+) T lymphocytes after stimulation with autoantigen (Ag) was significantly (>700-fold) increased with a concomitant increase in expression of the Foxp3 regulatory gene. Expression of OX40 was increased (maximum 11-fold) after allo-Ag via mixed-lymphocyte reaction response. CsA suppressed the upregulation of OX40 expression after allo-Ag in a dose-dependent manner. Taken together, these results suggest that the decrease in OX40 expression posttransplant includes the defective reconstitution of Treg cells, and the active inhibition of gene transcription by CsA.