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and not CD4
+
, T cells were the primary source of IL-17 and IL-21 produc-
tion after transplantation. Donor CD8
+
T-cell-derived IL-17A production
after G-CSF treatment was shown to be important for promoting macro-
phage infiltration and the subsequent development of cutaneous fibrosis,
which is one of the hallmarks of chronic GVHD in humans. Thus, these
studies identified IL-17 as a proximate mediator for sclerodermatous skin
changes during GVHD.
A putative role for IL-17 in the pathogenesis of chronic GVHD of the skin
is supported by more recent studies, which were conducted using a B10.
D2 → Balb/c murine model in which recipients develop skin pathology
that is also observed in human chronic GVHD. The authors demonstrated
that systemic manifestations, and more specifically, skin changes, were
significantly attenuated in recipients that received IL-17
−/−
donor T cells
[74]
. Thus, unlike in acute GVHD, transplantation with IL-17-deficient
grafts reduced the severity of GVHD. However, this was observed only in
the skin and salivary glands, whereas there was no difference in pathologi-
cal damage in the lung, liver, or colon. Notably, the attenuation of cutane-
ous pathology was observed in animals transplanted with IFN-γ-deficient
grafts as well, indicating that both cytokines appeared to have a role in the
pathology in this strain combination. Both studies therefore implicated a
role for IL-17 in the induction of fibrosis in the skin, but whether pathol-
ogy in other tissue sites is attributable to IL-17 is still unclear. These studies
also serve to highlight the fact that the murine models used to address the
role of IL-17 are an important variable. For example, in studies conducted
by Chen and colleagues
[71]
, the skin is not prominently involved during
chronic GVHD, while in the B10.D2 → Balb/c model, fur loss and skin lesions
are the major clinical manifestations. Furthermore, in the current study,
the authors found that mice that received IL-17
−/−
grafts had significantly
decreased frequencies of IFN-γ
+
cells in peripheral lymph nodes in the late
phase of the disease compared with recipients of wild-type cells, while in
the studies by Chen et al.
[71]
, no significant difference was observed in the
frequency of CD4
+
IFN-γ
+
T cells between recipients of IL-17
−/−
or wild-type
T cells. Therefore, in the absence of donor IL-17, Th1 responses were pre-
served in one study but were reduced in the second, which may explain, to
some extent, the outcomes and conclusions.
280
Roles of cytokines that induce Th17 differentiation
in GVHD
The cytokines TGF-β, IL-23, and IL-6 have all been shown to be involved in
the differentiation of Th17 cells from naïve T cells and/or the subsequent
expansion and maintenance of this helper T-cell population. Within recent
years, a number of studies have been performed in an attempt to determine
the roles of these cytokines in the pathophysiology of GVHD biology.
Interleukin 23
IL-23 was thought to be required for the differentiation of naïve T cells into
Th17 cells when it was first described
[10]
, but subsequent studies deter-
mined that this was incorrect
[20,22,23]
. Rather, IL-23 appears to be necessary
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