Stem cell mobilization with G-CSF induces type 17 differentiation and promotes scleroderma.
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.
Hill
Geoffrey R
GR
Queensland Institute of Medical Research, Brisbane, Australia;
Olver
Stuart D
SD
Kuns
Rachel D
RD
Varelias
Antiopi
A
Raffelt
Neil C
NC
Don
Alistair L
AL
Markey
Kate A
KA
Wilson
Yana A
YA
Smyth
Mark J
MJ
Iwakura
Yoichiro
Y
Tocker
Joel
J
Clouston
Andrew D
AD
Macdonald
Kelli P A
KP
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
D016207:Cytokines; D020381:Interleukin-17; D007378:Interleukins; D000098546:Interleukin-21