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 Blood, 1 May 2006, Vol. 107, No. 9, pp. 3430-3435.
Prepublished online as a Blood First Edition Paper on December 27, 2005; DOI 10.1182/blood-2005-10-4299.

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PERSPECTIVES

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

Edward S. Morris, Kelli P. A. MacDonald, and Geoffrey R. Hill

From the Bone Marrow Transplantation Laboratory, Queensland Institute of Medical Research, Queensland, Australia.

Abstract

The separation of graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) remains the "holy grail" of allogeneic stem cell transplantation, and improvements are urgently needed to allow more effective therapy of malignant disease. The use of G-CSF–mobilized peripheral blood as a clinical stem cell source is associated with enhanced GVL effects without amplification of significant acute GVHD. Preclinical studies have demonstrated that G-CSF modulates donor T cell function before transplantation, promoting 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 pattern of T cell differentiation after transplantation. Although these patterns of T cell differentiation attenuate acute GVHD, they do not have an impact on the cytolytic 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.


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