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donor CD4 cells of Th2 cytokine phenotype, generated by treating mice
in vivo
with a combination of IL-2 and IL-4, prevent lipopolysaccharide
(LPS)-induced, TNF-α-mediated lethality during a graft-versus-host reac-
tion
[50]
. The co-infusion of donor Th2 cells with naïve T cells also protects
recipient mice from GVHD lethality in an irradiated murine bone marrow
transplantation (BMT) model, supporting a regulatory role of Th2-type cells
in GVHD
[51]
. Finally,
in vitro
-polarized Th2 alloreactive donor T cells have
been shown to inhibit Th1 responses
in vivo,
and such inhibition attenuates
the systemic morbidity of GVHD after BMT across both major histocompat-
ibility complex (MHC) class I and class II barriers in mice
[52]
. These studies
support the notion that Th1 cells are the major pathogenic population and
polarization toward Th2 or co-infusion of Th2 cells downregulates GVHD.
However, interestingly, neutralization of selected Th1 cytokines, such as
IFN-γ, has not resulted in uniform protection from GVHD
[53,54]
. Rather,
discordant effects have been observed when donor cells deficient in their
ability to make IFN-γ have been transplanted into recipient animals. Spe-
cifically, this has resulted in protection in the gastrointestinal (GI) tract but
exacerbation of pathological damage in the lung
[55]
. These results indi-
cated an underlying complexity to the pathophysiology of GVHD and raised
the question as to whether other CD4
+
T-cell populations might also play a
role in GVHD biology. This has been, in part, the genesis for the examina-
tion of the role of Th17 cells in the pathogenesis of GVHD.
275
When considering the effects of IL-17 in GVHD biology, one needs to distin-
guish between the cytokine itself and the helper T-cell population known
as Th17 cells. This distinction is important because Th17 cells secrete a
number of cytokines (e.g., IL-22, IL-21, IL-17F) in addition to IL-17A. Thus,
simply equating Th17 cells with the secretion of IL-17 is an oversimplifica-
tion of the role that these cells may indeed play in the pathophysiology of
GVHD. For the purposes of this chapter, unless otherwise specified, IL-17
refers to IL-17A and should be considered distinct from other IL-17 cytokine
family members.
A requirement for IL-17 in the pathogenesis of acute GVHD has been for-
mally examined in several studies in which mice deficient in the secretion
of this cytokine were employed as donor animals in transplant experiments.
The first report by Yi and colleagues
[56]
employed a B6 → Balb/c transplan-
tation model and somewhat surprisingly showed that animals transplanted
with IL-17
−/−
grafts had more severe diarrhea and weight loss and signifi-
cantly reduced survival compared to recipients transplanted with grafts
from wild-type donors. Furthermore, serum IFN-γ and TNF-α levels were
significantly elevated in the former animals and this was accompanied
by a significant increase in donor IFN-γ-secreting CD4
+
and CD8
+
T cells
in both mesenteric lymph nodes and spleen, indicative of enhanced Th1
differentiation by IL-17
−/−
donor T cells. Neutralization of IFN-γ by
in vivo
administration of a blocking antibody or supplementation of exogenous
IL-17 protected mice from an exacerbation of GVHD lethality by inhibit-
ing Th1 differentiation. Thus, whereas the selective absence of donor IFN-γ
production has been shown to exacerbate GVHD in certain tissue sites such
as the lung
[55]
, blockade of IFN-γ signaling under conditions where there
was concurrent IL-17 deficiency was actually able to mitigate the severity
of GVHD. Similarly, the fact that the exogenous administration of IL-17 was
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