Induction of natural killer T cell–dependent alloreactivity by administration of granulocyte colony–stimulating factor after bone marrow transplantation

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Abstract

Granulocyte colony–stimulating factor (G-CSF) is often used to hasten neutrophil recovery after allogeneic bone marrow transplantation (BMT), but the clinical and immunological consequences evoked remain unclear1. We examined the effect of G-CSF administration after transplantation in mouse models and found that exposure to either standard G-CSF or pegylated-G-CSF soon after BMT substantially increased graft-versus-host disease (GVHD). This effect was dependent on total body irradiation (TBI) rendering host dendritic cells (DCs) responsive to G-CSF by upregulating their expression of the G-CSF receptor. Stimulation of host DCs by G-CSF subsequently unleashed a cascade of events characterized by donor natural killer T cell (NKT cell) activation, interferon-γ secretion and CD40-dependent amplification of donor cytotoxic T lymphocyte function during the effector phase of GVHD. Crucially, the detrimental effects of G-CSF were only present when it was administered after TBI conditioning and at a time when residual host antigen presenting cells were still present, perhaps explaining the conflicting and somewhat controversial clinical studies from the large European and North American BMT registries2,3. These data have major implications for the use of G-CSF in disease states where NKT cell activation may have effects on outcome.

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Figure 1: Administration of G-CSF or peg–G-CSF following bone marrow transplantation increases GVHD.
Figure 2: Administration of G-CSF after BMT activates donor NKT cells and enhances GVHD in an NKT cell− and CD8+ T cell–dependent manner.
Figure 3: G-CSF treatment after BMT increases NKT cell–dependent GVHD via effects on residual host tissue.
Figure 4: Conditioning with TBI, but not chemotherapy, enhances G-CSFR expression on host DCs and exacerbates GVHD after G-CSF administration.

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Acknowledgements

We thank D.C. Link (Washington University) and A.W. Roberts (The Walter and Eliza Hall Institute, Melbourne) for the Csf3r−/− mice and D. Pellicci (University of Melbourne) for the generation of CD1d tetramers used in this study. The TEa mice were supplied by J. Bromberg (Mount Sinai School of Medicine, New York). K.P.A.M. and C.R.E. are National Health and Medical Research Council (NHMRC) R.D. Wright Fellows. D.I.G. and M.J.S. are NHMRC Research Fellows. G.R.H. is a NHMRC Practitioner Fellow.

Author information

E.S.M. designed and performed experiments and contributed to the manuscript. K.P.A.M., R.D.K., H.M.M., T.B., A.L.J.D., V.R., Y.A.W., N.C.R., A.C.B. and K.A.M. performed experiments. C.R.E. contributed reagents and data interpretation. D.I.G. and M.J.S. contributed vital reagents and experimental design and contributed to the manuscript. G.R.H. designed the study and wrote the manuscript.

Correspondence to Geoffrey R Hill.

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Competing interests

The bone marrow transplantation laboratory has previously received funding from Amgen USA.

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