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autoimmune mice after adoptive transfer. The cotransfer of purified donor-
type Tregs completely protected mice and led to a substantial reduction
in the absolute number of IFN-γ- and IL-17-producing CD4
+
T cells, con-
firming that loss of effective regulation was responsible for autoimmune-
mediated pathology. Notably, the majority of Th17 cells identified in this
chronic GVHD model produced both IFN-γ and IL-17. This finding has been
observed in acute GVHD
[58]
as well as other autoimmune disease models
in which CD4
+
IL-17
+
IFN-γ
+
T cells have been postulated to have an etiologi-
cal role in the pathogenesis of the disease
[70]
. Whether this population has
a unique inflammatory role in GVHD biology will require further study.
In subsequent studies, we examined whether there was an obligate require-
ment for donor-derived IL-17 production in GVHD-associated autoim-
munity. Using a combination of antibody-based and genetic approaches,
we observed that IL-17 was not required for the loss of self-tolerance and
resulting CD4
+
T-cell-dependent pathologic damage that occurs during
the evolution from acute to chronic GVHD
[71]
. Specifically, anti-IL-17
antibody treatment had no effect on the development of autoimmunity
in recipient mice. Moreover, no difference was observed in the percent-
age of CD4
+
IL-17
+
or CD4
+
IFN-γ
+
T cells in either the spleen or the colon
of anti-IL-17- versus isotype antibody-treated mice, indicating that anti-
IL-17 antibody administration did not appear to alter the differentiation
of naïve T cells into IL-17- or IFN-γ-secreting CD4
+
T cells. Similar results
were observed when IL-17-deficient animals were employed as donors in
these experiments. Collectively, these studies demonstrated that IL-17 is
not required for the induction of pathologic damage and that Th1 cells and
other proinflammatory cytokines appear to be fully competent to promote
GVHD-associated autoimmunity. These studies, did not, however, define
the precise role of IL-17 in this process or the extent to which IL-17 and
IFN-γ may cooperatively function to induce disease.
279
G-CSF is a cytokine widely used in allogeneic hematopoietic stem cell
transplantation. G-CSF-mobilized peripheral stem cell transplantation is
associated with several favorable outcomes such as faster hematopoietic
reconstitution, improved graft-versus-leukemia (GVL) effect, and similar
severity of acute GVHD despite higher T-cell number infused compared
with traditional bone marrow transplantation
[72]
. However, this treatment
is also associated with increased chronic GVHD
[72]
. A recent study by Hill
and colleagues has provided a potential explanation for some of these
observations
[73]
and thereby delineated a new role for IL-17 in chronic
GVHD. In this study, the authors observed that G-CSF treatment of donor
mice promoted the generation of Th17 cells as demonstrated by enhanced
production of the signature cytokines IL-17A and IL-17F. G-CSF triggered IL-
17A production in both CD4
+
and CD8
+
T-cell populations, with enhanced
production of IL-17A in the absence of CD8
+
T cells. Interestingly, G-CSF
promoted Th17 differentiation independently of cytokines TGF-β and IL-6,
two cytokines widely reported to induce Th17 cell generation. Instead, IL-21
was critically important because the absence of IL-21 signaling completely
abolished the enhancement of IL-17 production. When G-CSF-mobilized
cells were used for transplantation, there was IL-17A-dependent patho-
logic damage observed in the skin of recipient animals, whereas GVHD of
the gastrointestinal tract was IL-17A-independent. Notably, donor CD8
+
,
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