title: Stem cell mobilization with G-CSF induces type 17 differentiation and promotes scleroderma.
abstract: The recent shift to the use of stem cells mobilized by granulocyte colony-stimulating factor (G-CSF) for hematopoietic transplantation has increased chronic graftversus-host disease (GVHD), although the mechanisms of this are unclear. We have found that G-CSF invokes potent type 17 rather than type 1 or type 2 differentiation. The amplification of interleukin-17 (IL-17) production by G-CSF occurs in both CD4 and CD8 conventional T cells and is dependent on, and downstream of, G-CSF-induced IL-21 signaling. Importantly, donor IL-17A controls the infiltration of macrophages into skin and cutaneous fibrosis, manifesting late after transplantation as scleroderma. Interestingly, donor CD8 T cells were the predominant source of IL-17A after transplantation and could mediate scleroderma independently of CD4 T cells. This study provides a logical explanation for the propensity of allogeneic stem cell transplantation to invoke sclerodermatous GVHD and suggests a therapeutic strategy for intervention.
authors.affiliation: Queensland Institute of Medical Research, Brisbane, Australia;
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Hill
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Olver
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Kuns
authors.forename: Antiopi
authors.initials: A
authors.lastname: Varelias
authors.forename: Neil C
authors.initials: NC
authors.lastname: Raffelt
authors.forename: Alistair L
authors.initials: AL
authors.lastname: Don
authors.forename: Kate A
authors.initials: KA
authors.lastname: Markey
authors.forename: Yana A
authors.initials: YA
authors.lastname: Wilson
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Joel
authors.initials: J
authors.lastname: Tocker
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Clouston
authors.forename: Kelli P A
authors.initials: KP
authors.lastname: Macdonald
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D003433:Crosses, Genetic; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D005355:Fibrosis; D006086:Graft vs Host Disease / Q000209:etiology*; D019650:Hematopoietic Stem Cell Mobilization / Q000009:adverse effects*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism / Q000502:physiology*; D007378:Interleukins / Q000502:physiology*; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D011828:Radiation Chimera; D012594:Scleroderma, Localized / Q000209:etiology*; D015398:Signal Transduction; D012867:Skin / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000637:transplantation*; D014184:Transplantation, Homologous / Q000009:adverse effects; D000098546:Interleukin-21
chemical_list: D016207:Cytokines; D020381:Interleukin-17; D007378:Interleukins; D000098546:Interleukin-21