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In-Depth Information
Th17 cells have been demonstrated to have both protective and pathogenic
effects, depending on the inflammatory microenvironment: i.e., the pres-
ence of IL-23 is thought to drive a pathogenic Th17 phenotype in experi-
mental models of autoimmunity, whereas TGF-β and IL-6 in the absence of
IL-23 are thought to promote immunomodulatory Th17 effects
[157,158]
.
Data suggest that Th1 and Th17 responses are reciprocally regulated: Th17
differentiation is inhibited by the Th1 cytokine IFN-γ
[159]
and Th2 cyto-
kines (e.g., IL-4 and IL-5) also suppress the development of Th17 cells. Addi-
tionally, IL-23 signaling downregulates IL-12 expression via the inhibition
of both IL-12p40 and IL-12p35 expression, serving to further promote Th17
at the expense of Th1 differentiation
[160]
. IL-23 itself is produced pre-
dominantly by antigen-presenting cells and signals via the IL-23R to pro-
mote Th17 differentiation (with additional signaling support from TNF and
IL-1β). IL-21 (which is discussed separately below) can assist in amplifying
Th17 differentiation in an IL-6-independent fashion, when it is present in
high concentrations in conjunction with TGF-β.
PRECLINICAL EVIDENCE FOR IL-17 AND IL-23 IN GVHD AND GVL EFFECTS
The first preclinical papers studying IL-17 in GVHD were published in 2009,
as appropriate reagents to study this relatively newly discovered cytokine
became available. Most reports so far highlight that donor-derived IL-17A
makes a pathological contribution to GVHD, particularly in the skin and
lung
[161,162]
. Importantly, it has been demonstrated that G-CSF pro-
motes type 17 differentiation within both conventional CD4
+
and CD8
+
populations and that this effect is downstream of IL-21 signaling. Of note,
scleroderma/chronic skin GVHD presents late after HSCT in these model
systems and the majority of IL-17A generated at this time point is from
CD8
+
T cells, and the disease process has been confirmed to be CD8 depen-
dent
[162]
. It is hypothesized that IL-17 controls the migration of fibrogenic
populations, particularly granulocytes and monocytes/macrophages to
target tissue.
375
Secretion of IL-23 by donor-type APC has been identified as an impor-
tant contributor to GVHD, specifically within the colon
[163]
. In this study
researchers also found that LPS translocation and proinflammatory cyto-
kine production (e.g., IFN-γ), both in serum and within the colon microen-
vironment, was markedly reduced in the absence of IL-23 production. The
same group later reported that blockade of IL-23 with an antibody directed
against the cytokine could protect mice from colonic GVHD while main-
taining GVL responses
[164]
. These data suggest that IL-23 has some effects
that are IL-17 independent.
CLINICAL EVIDENCE FOR IL-17/IL-23
The frequency of Th17 cells in the peripheral blood has been observed
to be increased in patients with aGVHD compared with either healthy
donors or allogeneic HSCT recipients without GVHD
[165]
. This corre-
lated with increased levels of IL-17 in the plasma, but only in patients
with active GVHD (compared to non-GVHD patients or healthy donor
controls). It is important to note that two other studies have been pub-
lished that failed to correlate IL-17 with aGVHD of either the skin or the
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