Perspective Stem cell mobilization with G-CSF analogs: a rational approach to separate GVHD and GVL?

The separation of graft-versus-host dis-ease (GVHD) and graft-versus-leukemia (GVL) remains the “holy grail ” of alloge-neic stem cell transplantation, and im-provements are urgently needed to allow more effective therapy of malignant dis-ease. The use of G-CSF–mobilized periph-eral blood as a clinical stem cell source is associated with enhanced GVL effects without amplification of significant acute GVHD. Preclinical studies have demon-strated that G-CSF modulates donor T cell function before transplantation, pro-moting TH2 differentiation and regulatory T cell function. In addition, the expansion of immature antigen-presenting cells (APCs) and plasmacytoid dendritic cells (DCs) favors the maintenance of this pat-tern of T cell differentiation after trans-plantation. Although these patterns of T cell differentiation attenuate acute GVHD, they do not have an impact on the cyto-lytic pathways of the CD8 T cells that are critical for effective GVL. Recently, it has been demonstrated that modification of G-CSF, either by pegylation of the native cytokine or conjugation to Flt-3L, results in the expansion and activation of donor iNKT cells, which significantly augment CD8 T cell–mediated cytotoxicity and GVL effects after transplantation. Given that these cytokines also enhance the expansion of regulatory T cells and APCs, they further separate GVHD and GVL, offering potential clinical advantages for the transplant recipient. (Blood. 2006