Bortezomib modulates regulatory T cell subpopulations in the process of acute graft-versus-host disease.

Abstract Acute graft-versus-host disease (aGVHD) combines the wide application of allogeneic bone marrow transplantation (allo-BMT). Recent studies indicate that it is possible to reduce the incidence and severity of aGVHD by using bortezomib. In this study, we explored the changes of T cell subsets after allo-BMT with bortezomib, in order to elucidate the mechanism by which bortezomib attenuates aGVHD. Following a single dose of lethal irradiation (TBI, 0.7 Gy/minutes, 8.0 Gy), BALB/c mice were injected with 2 x 10(7) C57BL/6 nucleated BM cells plus 1 x 10(7) splenocytes with or without bortezomib at 1.0 mg/kg. The ratio of CD4+CD25+ Foxp3+ regulatory T cells (Treg) was examined by flow cytometry, and the cytokine levels of IL-2 (Th1) and IL-4 (Th2) were detected by ELISA. Bivariate correlation analysis was carried out to evaluate changes of the Th1 and Th2 cytokines related to the changes of Treg. Bortezomib remarkably reduced aGVHD severity and prolonged the survival time. Along with bortezomib injection, the ratio of Treg was significantly increased and IL-2 level was decreased but IL-4 level was increased. Bivariate correlation analysis results evaluated the correlation between the increment of Treg and changes of Th1 and Th2 cytokines. Bortezomib may exert its effect by triggering the generation of Treg which might regulate the imbalance of Th1/Th2 during aGVHD.