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for the maintenance of effector function
in vivo
[21]
. This cytokine has also
been shown to play a critical role in mediating pathological damage in several
mouse models of autoimmunity
[11-13]
, which is a characteristic of GVHD.
Furthermore, a linkage between IL-23 and autoimmunity has been strength-
ened by a considerable body of genetic evidence in humans that links IL-23R
polymorphisms with susceptibility to a range of autoimmune diseases such
as Crohn's disease, multiple sclerosis, and psoriasis
[75-77]
. For these rea-
sons, studies were performed in our lab to examine the role of IL-23 in the
biology of GVHD. We observed that IL-23 has a unique and selective role in
the induction of colonic inflammation during acute GVHD and serves as a
critical mediator linking conditioning regimen-induced mucosal injury and
LPS translocation to subsequent proinflammatory cytokine production and
GVHD-associated pathological damage
[61]
. Specifically, transplantation
of IL-23-deficient marrow grafts significantly reduced the severity of acute
GVHD, which was attributable to the preferential reduction in colonic GVHD
and a decrease in the production of proinflammatory cytokines within this
tissue site. Secretion of IL-23 by donor, and not host, antigen-presenting cells
was shown to be a critical event in the induction of GVHD of the colon. These
findings indicated a novel organ-specific role for IL-23 in the pathophysiol-
ogy of GVHD and demonstrated that IL-23 can direct tissue-specific pathol-
ogy within the context of a systemic inflammatory disorder. Interestingly,
while the majority of experimental colitis models have implicated Th17 cells
as the downstream effectors of IL-23-induced mucosal pathology
[11,78,79]
,
these studies did not reveal a role for IL-17 in the pathophysiology of GVHD
in the colon. Elevated levels of IL-23 were not accompanied by correspond-
ing increases in IL-17 in the colon microenvironment, and IL-17 mRNA levels
were virtually undetectable in the colons of these same animals. CD4
+
IL-17
+
cells were also present only in negligible numbers in the spleen, liver, and
colon of GVHD animals. Furthermore, transplantation with marrow grafts
from IL-17
−/−
donors had no protective effect on either overall or colon-
specific GVHD-associated pathology, providing evidence that the proin-
flammatory effects of IL-23 were independent of IL-17. Rather, these studies
indicated that the downstream proinflammatory effects of IL-23 were depen-
dent upon donor-derived secretion of IFN-γ, as the absolute number of CD4
+
IFN-γ
+
cells in the colon was significantly increased relative to CD4
+
IL-17
+
cells. Moreover, transplantation with IL-23
−/−
marrow grafts resulted in a pro-
found reduction in CD4
+
IFN-γ
+
T cells compared with recipients of wild-type
grafts, further implicating a role for these cells in colonic GVHD. These results
confirmed that mucosal pathology mediated by IL-23 could occur in a Th17-
independent manner, which has been reported in nontransplant studies,
supporting the existence of an alternative pathway whereby the proinflam-
matory effects of IL-23 in the colon are mediated through secretion of IFN-γ
[80,81]
.
281
The role that donor-derived IL-23 production has in GVHD was confirmed
by Thompson and colleagues
[82]
, who showed that transplantation with
IL-23-deficient grafts reduced GVHD mortality. In this study, however, IL-17
mRNA levels were increased in the spleen of GVHD control animals when
examined early post-transplantation. This discrepancy, however, may be
explainable by the fact that IL-17 mRNA levels were elevated only on days
5-7 and then quickly declined by day 10 to where they were not different
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