Role of Th17 cells and interleukin 17 in graft-versushost disease and graft-versusleukemia reactivity - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 280

the expansion and/or differentiation of Th1 cells. Similar results have been
reported before in a model of experimental allergic encephalomyelitis [87] .
These results are consistent with earlier data demonstrating an increase in
iTregs and a decline in Th1 and Th17 cells in the absence of IL-6 [31] . Pro-
tection from GVHD by way of IL-6 blockade has been recently confirmed
by Tawara and colleagues [88] . In addition, they demonstrated that the GVL
effect could also be preserved in animals that were protected from lethal
GVHD. However, a notable difference between the two studies was that the
latter did not observe an increase in Treg reconstitution after BMT. This dis-
crepancy could be due to a different antibody dosing and administration
schedule, which could have affected Treg regeneration. It should be noted
that blockade of IL-6/IL-6R interactions is currently a clinically feasible
option given that Tocilizumab is an FDA-approved, humanized anti-IL-
6R antibody that has been administered to patients with rheumatoid and
juvenile arthritis. In fact, a recent study has demonstrated activity of Tocili-
zumab in patients with steroid-refractory GVHD [89] .

TGF- β

The role of TGF-β in experimental GVHD has been somewhat controver-
sial and complicated by the fact that this cytokine may have different roles
depending upon when it is secreted post-transplantation. Early studies in
a murine transplantation model of skin fibrosis (B10.D2 → Balb/c) dem-
onstrated that antibody blockade of TGF-β could prevent skin and lung
fibrosis in recipient animals [90] . While this is viewed as a model of chronic
GVHD, it should be noted that fibrotic changes were apparent within 21
days of transplantation, which is indicative of a much more rapid disease
course than seen in patients. Fibrosis in this model was prominently asso-
ciated with infiltration of mononuclear cells. Subsequent work by Banovic
et al. [91] indicates that the role of TGF-β may be more complex than ini-
tially appreciated. They observed that TGF-β had a protective effect early
post-transplantation that was mediated by donor T cells, whereas in the
later stages of GVHD, TGF-β production, primarily by mononuclear cells,
was responsible for manifestations of chronic GVHD. The observation that
mononuclear cells may be the proximate population involved in the induc-
tion of skin fibrosis is of interest and has been validated in subsequent
studies by this group [73] . Moreover, these results uncover a mechanism
that may be amenable to clinical intervention. Finally, a protective effect
of TGF-β during acute GVHD is supported by more recent studies, which
have investigated the role of Smad3 in GVHD pathogenesis. Smad3 is a
critical component of the TGF-β signaling pathway. These studies [92] dem-
onstrated that transplantation with Smad3 −/− marrow grafts resulted in an
acceleration in GVHD lethality and this was accompanied by an increase in
Th1 cells and granulocytes, which together released proinflammatory cyto-
kines and promoted tissue damage.

283

Roles of transcription factors involved in Th17 cell
differentiation in GVHD

Th17 cell differentiation is regulated by a series of transcription factors, spe-
cifically ROR-γt, ROR-α, IRF-4, and STAT3 [93,94] . The primary transcription