Research ArticleGraft-Versus-Host Disease

G-CSF mobilizes CD34+ regulatory monocytes that inhibit graft-versus-host disease

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Science Translational Medicine  01 Apr 2015:
Vol. 7, Issue 281, pp. 281ra42
DOI: 10.1126/scitranslmed.3010435

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Monocytes suppress GVHD

Hematopoietic stem cell transplantation is a highly successful therapy used in patients with bone marrow dysfunction. However, when the stem cell donor cannot be matched to the recipient, the transplanted cells may attack the host in a process called graft-versus-host disease (GVHD). D’Aveni et al. now show that granulocyte colony-stimulating factor (G-CSF)–mobilized stem cells contain a previously uncharacterized population of immunosuppressive CD34+ cells transcriptionally similar to mature monocytes. These cells induce allogeneic T cell death in response to interferon-γ, resulting in regulatory T cell expansion and immunosuppression. The fraction of these CD34+ monocytes in peripheral blood inversely correlates with GVHD in patients, suggesting that expanding these cells before transplant may decrease the risk of GVHD.

Abstract

Granulocyte colony-stimulating factor (G-CSF) is routinely used to collect peripheral blood stem cells (PBSCs) from healthy donors for allogeneic hematopoietic stem cell transplantation (allo-HSCT). We show that, in both humans and mice, G-CSF mobilizes a subset of CD34+ cells with mature monocyte features. These cells, which are phenotypically and functionally conserved in mice and humans, are transcriptionally distinct from myeloid and monocytic precursors but similar to mature monocytes and endowed with immunosuppressive properties. In response to interferon-γ released by activated T cells, these cells produce nitric oxide, which induces allogeneic T cell death both in vitro and in vivo. These apoptotic T cells are engulfed by macrophages that release transforming growth factor–β and promote regulatory T cell expansion. Indeed, the fraction of CD34+ monocytes in peripheral blood CD34+ cells inversely correlates with the incidence of acute graft-versus-host disease (GVHD) in humans. Therefore, G-CSF–mobilized cells are an attractive candidate population to be expanded ex vivo for cellular therapy against GVHD.

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