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been most extensively examined with respect to GVHD biology. IL-21 is
expressed by a variety of cell types including T cells, B cells, NK cells, den-
dritic cells, macrophages, and epithelial cells
[118]
. Relevant to this chapter
is the fact that IL-21 is secreted by Th17 cells and also aids in the differentia-
tion of these cells via an alternative IL-6-independent pathway
[30]
. In the
context of GVHD, several groups have examined the role of IL-21 in GVHD
biology in murine transplantation models
[119-122]
. For the most part, all
studies have demonstrated that interruption of IL-21 signaling by either
antibody-based strategies or genetic approaches is able to attenuate the
severity of GVHD. The mechanisms by which this occurs have varied and
include augmentation of Treg reconstitution and decreased expansion of
donor effector T cells, indicating that blockade of IL-21 signaling appears to
result in a recalibration of the effector and regulatory arms of the immune
system. The augmentation of Tregs in the setting of IL-21 blockade has been
reported for both nTregs and iTregs. Notably, GVHD protection has been
observed selectively in the gastrointestinal tract in at least one study
[121]
,
which is similar to what has been reported for IL-23. Of interest, both cyto-
kines signal through STAT3, raising the question as to whether this pathway
is particularly important in mediating pathological damage in the colon
microenvironment. More recently, IL-21 blockade has also been shown to
be effective in preventing GVHD mortality in a xenogeneic model of GVHD
[123]
. Notably, in contrast to prior mouse models, blocking of IL-21 resulted
in a decreased percentage of IL-17
+
cells, indicating that IL-21 inhibition
may reduce GVHD in humans, in part, by preventing differentiation of Th17
cells. Furthermore, colon and skin samples obtained from patients with
active GVHD revealed increased IL-21 expression in mononuclear cells rel-
ative to samples acquired from patients with no GVHD. Collectively, these
results provide support for the premise that IL-21 has a role in mediating
GVHD pathology in humans as well.
289
Interleukin 17F
There are a number of other IL-17 family members, which have been termed
IL-17B, C, D, E, and F. The most homologous to IL-17A is IL-17F, which is also
produced by Th17 cells as well as innate immune cells and epithelial cells.
IL-17A and IL-17F can form heterotrimers, and the pairing of IL-17A and
IL-17F as homodimers or heterotrimers can affect their immune function
[124]
. The roles of these cytokines have been shown to be overlapping yet
distinct with respect to the induction of autoimmunity and production of
cytokines
[34]
. IL-17F has not been specifically examined within the context
of GVHD, although as noted previously,
in vitro
-generated Th17 cells that
mediated lethal GVHD comprised a subpopulation that secreted IL-17F
[59]
. However, transferred Th17 cells recovered from GVHD target organs
in this study had lost expression of IL-17F. Thus, whether IL-17F promotes
pathological damage or synergizes with IL-17A is not known.
Interleukin 22
IL-22 is a novel cytokine in that it is secreted by immune cells such as Th17
cells, NK cells, LTi cells, and NKT cells, but acts specifically on epithelial
cells
[125]
. Prior studies have defined both proinflammatory and anti-
inflammatory roles for this cytokine in various tissue sites such as the liver
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