Abstract
The clinical shift toward utilizing G-CSF mobilized stem cell grafts has resulted in a striking increase in chronic GVHD after transplantation although the mechanisms involved are unclear. Comparison of cytokine expression following TCR activation of splenocytes from naïve and G-CSF treated B6 or BALB/c donors (low and high responders respectively) showed little effect of G-CSF on Th1 or Th2 cytokine production. In contrast, IL-17 production was dramatically enhanced in response to G-CSF in both strains. G-CSF induced IL-17 production occurred in both CD4 and CD8 conventional T cells and by using relevant knock-out mice or blocking reagents we demonstrated that this was independent of IL-6, TGF-beta or IL-23 signalling. However, the induction of IL-17 by G-CSF was completely dependent on IL-21 signalling and G-CSF induced IL-21 generation in CD4 T cells independent of IL-17 itself. We utilized multiple models of GVHD using G-CSF mobilized B6 or BALB/c wild-type or IL-17 deficient donors, in both MHC matched and mismatched settings. Surprisingly, IL-17 was critical for the induction of sclerodermatous chronic GVHD occurring after transplant using either donor strain. Importantly, IL-17 controlled the dramatic sequestration of macrophages into skin that coincided with the fibrogenic response. 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.
