Stem cell mobilization with G-CSF induces Type-17 differentiation and promotes scleroderma
- Geoffrey R Hill1,
- Stuart D Olver1,
- Rachel D Kuns1,
- Antiopi Varelias1,
- Neil C Raffelt1,
- Alistair L Don1,
- Kate A Markey1,
- Yana A Wilson1,
- Mark J Smyth2,
- Yoichiro Iwakura3,
- Joel Tocker4,
- Andrew D Clouston5, and
- Kelli PA MacDonald1,*
- 1 The Queensland Institute of Medical Research, Brisbane, QLD, Australia;
- 2 Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, St Andrews Place, Vic, Australia;
- 3 Center for Experimental Medicine, Institute of Medical Science, the University of Tokyo, Tokyo, Japan;
- 4 Amgen, Seattle, WA, United States;
- 5 Envoi Pathology, Brisbane, QLD, Australia
- * Corresponding author; email: kelli.macdonald{at}qimr.edu.au
Abstract
The recent shift to the use of stem cells mobilized by granulocyte colony-stimulating factor (G-CSF) for hematopoietic transplantation has increased chronic graft-versus-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 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 signalling. Importantly, donor IL-17A controlled the infiltration of macrophages into skin and cutaneous fibrosis, manifesting late after transplant 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.
- Submitted November 30, 2009.
- Accepted April 8, 2010.
- Copyright © 2005 American Society of Hematology
