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Another group has reported that host NKT cell-derived IL-4 is effective at
reducing aGVHD, via an effect on expansion of donor Tregs
[109]
. The Th2
cytokines, including IL-4 and IL-13 (discussed further below), are pathogenic
particularly in the lung during GVHD, as demonstrated using donor cells
incapable of producing either Th1 or Th17 cytokines, and thus forced down
the Th2 differentiation pathway
[16]
.
In vitro
treatment of donor-type T cells
with rapamycin (Sirolimus) has been demonstrated to generate Th2 cells that
can protect from GVHD because of their specific production of IL-4, despite
reduced levels of the other Th2 cytokines IL-5, IL-10, and IL-13
[110]
.
CLINICAL EVIDENCE FOR IL-4
A small study of cGVHD patients demonstrated that the proportion of
CD8-expressing T cells secreting IL-4 was significantly higher in patients
with cGVHD compared to a control patient cohort
[111]
. Despite protective
effects of IL-4 seen in aGVHD, it is possible that IL-4 contributes to fibrosis
in cGVHD via IL-13 induction and thus it is difficult to envisage a clinical
therapy designed around the administration of IL-4 at this stage.
IL-13
371
IL-13, like IL-4, is a classical Th2 cytokine and also relies on STAT6 for intra-
cellular signaling. It is, of course, produced by CD4
+
Th2 cells, but can also be
produced by activated T cells (both CD4 and CD8) of other lineages, as well
as mast cells and B cells
[112]
. The surface receptor for IL-13 has two known
chains: the IL-13Rα1 and the IL-13Rα2. The α1 chain is a low-affinity recep-
tor that dimerizes with the IL-4Rα chain to form a high-affinity receptor and
initiate IL-13 signaling. The IL-13Rα2 is a high-affinity receptor; however,
interestingly it does not always mediate signaling as it can be internalized
immediately after binding to IL-13, thus acting as a decoy receptor. There
are also reports that it can act as a functional receptor, and when this is the
case, it utilizes the same STAT6-dependent pathway as the IL-13Rα1:IL-4Rα
and induces the same functional effects
[113]
. IL-13 induces tissue fibrosis
by stimulating TGF-β production
[114]
. It can also act to enhance secretion
of mucus by lung parenchyma and induce bronchial spasm. This can lead
to blockage of the respiratory tract and result in respiratory failure
[115]
.
In a study examining the role of T-bet (a Th1-associated transcription fac-
tor) in a mouse model of pulmonary GVHD, IL-17 and IL-13 were increased
relative to controls, and it was determined that the T-bet-driven Th1 cyto-
kines were dispensable for lung GVHD development
[116]
. IL-13 has also
been shown to promote arginase-1 expression in myeloid suppressor cells
and thereby inhibit GVHD
[117]
. The authors also demonstrated that this
did not negatively influence GVL effects.
With respect to clinical evidence for IL-13, mixed lymphocyte cultures in
which donor PBMCs were stimulated with host PBMC prior to transplant
demonstrated that high production of IL-13 by donor cells after
in vitro
stimulation was associated with development of acute GVHD in transplant
recipients
[118]
. Like TGF-β (discussed below) it is likely that IL-13 has a
protective role early (due to its impact on myeloid suppressor cell function)
and a pathogenic role late after HSCT, due to its capacity to promote lung
pathology.
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