Early myeloid-derived suppressor cells (HLA-DR−/lowCD33+CD16−) expanded by granulocyte colony-stimulating factor prevent acute graft-versus-host disease (GVHD) in humanized mouse and might contribute to lower GVHD in patients post allo-HSCT

Abstract

Introduction

Myeloid-derived suppressor cells (MDSCs) are proposed to control graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the definition of human MDSCs has not yet reached consensus, and the mechanism of MDSCs to control GVHD remains unclear.

Methods

Immature myeloid cells (HLA-DR^−/lowCD33⁺CD16⁻) were tested before and after granulocyte colony-stimulating factor (G-CSF) administration in healthy donor and isolated for suppression assays and co-culture with T cells in vitro. Isolated cells were infused in humanized mice for a xenogeneic model of acute GVHD. One hundred allo-HSCT recipients were enrolled prospectively to assess the role of HLA-DR^−/lowCD33⁺CD16⁻ cells in grafts on the occurrence of acute GVHD.

Results

In the present study, G-CSF mobilized HLA-DR^−/lowCD33⁺CD16⁻ cells with immunosuppressive properties in donor peripheral blood. These cells contained more interleukin-10⁺ and transforming growth factor-beta (TGF-β)⁺ cells after G-CSF administration and inhibited the proliferation of autologous donor T cells in a TGF-β-dependent manner. Meanwhile, these immature myeloid cells promoted regulatory T cell expansion and induced Th2 differentiation. Importantly, these cells prevented acute GVHD in a humanized mouse model. Moreover, clinical cohort results showed that the number of HLA-DR^−/lowCD33⁺CD16⁻ cells in the donor graft was the only independent risk factor inversely correlated with the incidence of grade II–IV acute GVHD in the recipients (HR 0.388, 95% CI 0.158–0.954, p = 0.039).

Conclusion

HLA-DR^−/lowCD33⁺CD16⁻ cells represent functional MDSCs that may control acute GVHD in allo-HSCT.