title: Donor treatment with pegylated G-CSF augments the generation of IL-10-producing regulatory T cells and promotes transplantation tolerance.
abstract: We investigated whether the protection from graft-versus-host disease (GVHD) afforded by donor treatment with granulocyte colony-stimulating factor (G-CSF) could be enhanced by dose escalation. Donor treatment with human G-CSF prevented GVHD in the B6 --> B6D2F1 murine model in a dose-dependent fashion, and murine G-CSF provided equivalent protection from GVHD at 10-fold lower doses. Donor pretreatment with a single dose of pegylated G-CSF (peg-G-CSF) prevented GVHD to a significantly greater extent than standard G-CSF (survival, 75% versus 11%, P <.001). Donor T cells from peg-G-CSF-treated donors failed to proliferate to alloantigen and inhibited the responses of control T cells in an interleukin 10 (IL-10)-dependent fashion in vitro. T cells from peg-G-CSF-treated IL-10(-/-) donors induced lethal GVHD; T cells from peg-G-CSF-treated wild-type (wt) donors promoted long-term survival. Whereas T cells from peg-G-CSF wt donors were able to regulate GVHD induced by T cells from control-treated donors, T cells from G-CSF-treated wt donors and peg-G-CSF-treated IL-10(-/-) donors did not prevent mortality. Thus, peg-G-CSF is markedly superior to standard G-CSF for the prevention of GVHD following allogeneic stem cell transplantation (SCT), due to the generation of IL-10-producing regulatory T cells. These data support prospective clinical trials of peg-G-CSF-mobilized allogeneic blood SCT.
authors.affiliation: Queensland Institute of Medical Research, Herston, Australia.
authors.forename: Edward S
authors.initials: ES
authors.lastname: Morris
authors.forename: Kelli P A
authors.initials: KP
authors.lastname: MacDonald
authors.forename: Vanessa
authors.initials: V
authors.lastname: Rowe
authors.forename: Diana H
authors.initials: DH
authors.lastname: Johnson
authors.forename: Tatjana
authors.initials: T
authors.lastname: Banovic
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Clouston
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Hill
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000096:biosynthesis*; D051379:Mice; D008815:Mice, Inbred Strains; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000494:pharmacology*; D015996:Survival Rate; D013601:T-Lymphocytes / Q000187:drug effects* / Q000637:transplantation; D014019:Tissue Donors; D014184:Transplantation, Homologous
chemical_list: C486981:pegylated granulocyte colony-stimulating factor, human; D016753:Interleukin-10; D016179:Granulocyte Colony-Stimulating Factor; D011092:Polyethylene Glycols