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from those of wild-type mice. The study by Das et al.
[61]
, in contrast, exam-
ined levels at later time points beginning on day 7 and so it is possible that
IL-17 is only transiently upregulated during GVHD. It is still not clear at this
point whether the absence of IL-23 attenuates other effector molecules
downstream of IL-23 signaling, such as IL-21 and IL-22. Notably, blockade
of IL-23 signaling as a strategy to prevent GVHD may soon be able to be
examined in patients given that administration of a p19-specific antibody is
currently in clinical trials for patients with psoriasis. In that regard, Ustekun-
imab, which binds to p40, a common subunit of both IL-12 and IL-23, has
been administered recently to a patient with refractory GVHD with some
activity observed
[83]
. While blockade of p40 does not allow one to distin-
guish between the effects of IL-12 and IL-23, it does suggest a potential role
for IL-23 in the pathogenesis of GVHD in humans.
Interleukin 6
IL-6 is a proinflammatory cytokine that has been shown to be crucial in ini-
tiating a Th17 immune response. In the presence of IL-6 and TGF-β, naïve
T cells differentiate into Th17 cells, whereas in its absence these same cells
are induced to become Tregs
[22,23]
. Furthermore, IL-6 produced by den-
dritic cells after activation through Toll-like receptors is able to inhibit the
suppressive function of natural Tregs
[84,85]
. Thus, IL-6 appears to have
a pivotal role in directing the immune system toward an inflammatory
response. This is of particular interest with respect to GVHD biology since
the pathogenesis of GVHD is characterized by an imbalance between the
effector and the regulatory arms of the immune system. The role of IL-6
in GVHD biology has been examined by two groups. Chen and colleagues
[86]
performed experiments to examine how IL-6 contributed to the patho-
physiology of GVHD using antibody-mediated blockade of the IL-6 receptor
(IL-6R). These studies determined that blockade of IL-6 signaling markedly
reduced pathologic damage attributable to GVHD. This was accompanied
by a significant increase in the absolute number of Tregs that was due to
augmentation of both thymic-dependent and thymic-independent Treg
production. With respect to the latter population, it was observed that the
conversion of CD4
+
FOXP3
−
T cells to CD4
+
FOXP3
+
T cells in the spleen or
selected target organs during GVHD was very limited and insufficient to
prevent pathologic damage. Administration of anti-IL-6R antibody, how-
ever, resulted in a significant increase in both the percentage and the abso-
lute number of iTregs and this was associated with a marked reduction in
overall GVHD. Notably, GVHD protection that could be ascribed solely to
iTregs was observed only in the colon as there was no difference in pathol-
ogy scores in either the lung or the liver. This observation suggests that
iTregs may be of particular importance in regulating alloimmune reactions
in the gut and that IL-6 has a pivotal role in inhibiting this event. Blockade of
IL-6 signaling was also associated with a significant reduction in the num-
ber of Th17 cells in all tissue sites. These data indicate that blockade of IL-6
signaling was able to divert the differentiation of naïve T cells away from
the Th17 cell lineage into the Treg lineage and thereby serve to recalibrate
the effector and regulatory arms of the immune system. There was also
a significant reduction in the absolute number of CD4
+
IFN-γ
+
Th1 cells
as well in GVHD target organs, implying that blockade of IL-6 inhibited
282
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