Biology Reference
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and GI tract
[126,127]
. Notably, these tissues are also target organs during
GVHD, thus making the examination of this cytokine a reasonable area of
inquiry. A recently published report has shown that IL-22 plays a role in thy-
mic regeneration
[128]
, but whether IL-22 plays a role in mediating other
target organ damage during GVHD will require further study.
Role of IL-17 and Th17 cells in GVL reactivity
Because of the proinflammatory effects of IL-17, a number of investigators
have examined both IL-17 and Th17 cells to determine whether they have
a role in promoting anti-tumor immunity in nontransplant tumor mod-
els. IL-17 has been shown to be capable of promoting tumor growth and
metastasis in several different tumor models
[129,130]
. This has been asso-
ciated with increased angiogenesis and upregulation of prosurvival genes.
Interestingly, in one report, commensal organisms in the gut were able to
activate Th17 cells, which then led to the development of colon tumors in
predisposed animals
[131]
. Conversely, tumor-specific polarized Th17 cells
can mediate potent anti-tumor effects, indicating that augmented produc-
tion of IL-17 can in some instances eliminate malignant cells
[132]
. Thus,
it appears that IL-17 and Th17 cells can either promote tumorigenesis or
mediate anti-tumor immunity depending upon the experimental system.
In allogeneic stem cell transplantation, the role of IL-17, and Th17 cells, in
mediating a GVL effect has been much less well characterized than in cor-
responding studies that have been performed to elucidate the effect of this
cytokine in the pathogenesis of GVHD. There have been two reports
[57,96]
that have examined GVL responses in the larger context of the roles of Th17
cells and IL-17 in GVHD biology. These studies demonstrated that neither
IL-17 production nor the presence of ROR-γt was required for donor T cells
to mediate a GVL response. With respect to other Th17-related cytokines,
several studies have shown similar preservation of GVL effects when signal-
ing through either IL-21 or IL-23 is impaired by either antibody-based or
genetic approaches
[119,133]
. Thus, based on limited data in animal mod-
els, there appears to be no obligate requirement for Th17-related cytokines
to maintain an effective GVL response.
290
Summary
Results from a number of studies in experimental GVHD models have now
established that IL-17 and Th17 cells contribute to the pathophysiology of
both acute and chronic GVHD, although the extent and magnitude of this
contribution are still not resolved. Moreover, how these cells interact with
other resident T-cell populations in promoting the inflammatory cascade that
is the hallmark of GVHD remains to be elucidated. Perhaps the most intrigu-
ing aspect of these initial studies has been the emerging awareness that Th17
cells may have a unique role in mediating tissue-specific pathology, such as
cutaneous fibrosis and lung injury, which are particularly severe manifesta-
tions of chronic GVHD in patients. These observations could have significant
clinical implications and could open the door for IL-17-directed therapies
designed to address these complications. While the role of Th17 cells has yet
to be validated in human GVHD, there are some data that suggest that these
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