A glucocorticoid amplifies IL-2-induced selective expansion of CD4(+)CD25(+)FOXP3(+) regulatory T cells in vivo and suppresses graft-versus-host disease after allogeneic lymphocyte transplantation.

Regulatory T (Treg) cells are a subpopulation of T cells that not only prevent autoimmunity, but also control a wide range of T cell-dependent immune responses. Glucocorticoid treatment (dexamethasone, or Dex) has been reported to amplify IL-2-mediated selective in vivo expansion of Treg cells. We simultaneously administered Dex and IL-2 to the donor in a murine allogeneic lymphocyte transplantation model to expand functional suppressive CD4(+)CD25(+)FOXP3(+) T cells in the graft and to raise the regulatory T cell/effector T cell (Treg/ Teff ) ratio to prevent graft-versus-host disease (GVHD). After combined treatment of the donor with Dex (5 mg/kg/day) and IL-2 (300,000 IU/mouse/day) for 3 days, grafts were subjected to flow cytometric analysis, and transplantation was carried out from male C57BL/6 mice to female BALB/c mice aged 8-12 weeks. Results showed that short-term simultaneous administration of Dex and IL-2 markedly expanded functional suppressive CD4(+)CD25(+)FOXP3(+) T cells in the murine spleen. In this murine allogeneic transplantation model, the grafts from donors with Dex and IL-2 pre-treatment led to a longer survival time for the recipients than for the control group (median survival time > 60 day vs. 12 day, P=0.0002). The ratio of Treg/Teff also increased remarkably (0.43+/-0.15 vs. 0.14+/-0.01, P=0.01). This study demonstrated that co-stimulation with Dex and IL-2 selectively expanded functional CD4(+)CD25(+)FOXP3(+) T cells in vivo, and that grafts from donors pre-treated with Dex and IL-2 led to longer survival time and greater suppression of GVHD after allogeneic transplantation. Thus, GVHD can be suppressed by the specific expansion of regulatory T cells with Dex and IL-2 in graft donors.

[Combination of dexamethasone with IL-2 selectively induces the expansion of CD4(+)CD25(+)FOXP3(+) regulatory T cells in vivo and suppresses graft versus host disease.].

OBJECTIVE: To establish a method for increasing T regulatory cells (Treg) in the graft by using in vivo treatment with dexamethasone (Dex) plus IL-2 and observe its suppressing effect on graft-versus-host-disease (GVHD) in mice. METHODS: After treatment of male C57BL/6N mice (donor) with Dex (5 mgxkg(-1)xd(-1)) combined with IL-2 (300 000 IUxmouse(-1)xday(-1)) for three days, spleen mononuclear cells were isolated for flow cytometry analysis of CD4(+)CD25(+) POXP3(+) Treg cells. The allogeneic lymphocytes were transplanted from male C57BL/6N mice to female BALB/c mice aged 8-12 weeks. GVHD and survival time were investigated after transplantation. Donor-derived hematopoiesis reconstituted in recipient mice was detected by Y-chromosome-specific PCR and H-2K(b) by flow cytometry. RESULTS: Administration of Dex and IL-2 markedly expanded functional CD4(+)CD25(+)FOXP3(+) Treg cells in murine spleen, the number of which in treated group was (24.2 +/- 7.6)% while in control group was (4.0 +/- 0.8)% (P = 0.01). The ratio of Treg to effector T cells (Teff) increased obviously in the treated group (0.43 +/- 0.15 vs 0.14 +/- 0.01, P = 0.01). In a murine allogeneic lymphocyte transplantation model, the grafts from donor with combined treatment of Dex and IL-2 led to a longer survival time than that from the control group (median survival time > 60 d vs 12 d, P = 0.0045), while the mortality rate was decreased (29.4% vs 71.4%, P < 0.05). CONCLUSION: Costimulation with Dex and IL-2 can selectively expand the functional CD4(+)CD25(+)FOXP3(+) Treg in vivo, which can suppress acute GVHD.