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no difference in the proportion of IL-22-producing CD3
+
T cells between
patients with GVHD and without GVHD and healthy donors. However, in
contrast to intracellular cytokine data, when the amounts of IL-17 and IL-22
in the supernatant from peripheral blood mononuclear cells activated via
αCD3/CD28 antibody were measured, the levels of IL-17 were significantly
decreased in patients with GVHD compared to patients without GVHD. In
keeping with decreased IL-17 production, lower levels of IL-22 were detected
in patients with GVHD compared to patients without GVHD. The authors
reasoned that the lack of circulating IL-17-producing T cells might be attrib-
utable to preferential homing of these cells to GVHD target tissues such as
the skin. However, when skin-resident T cells isolated from cultured explants
from skin biopsies of patients with acute GVHD were analyzed, few IL-17
+
or
IL-22
+
CD4
+
T cells were present in the skin of patients with acute GVHD. The
proportion of CD4
+
T cells expressing CCR4 or CCR6, characteristic homing
markers of Th17 cells, was also significantly lower in skin from patients with
GVHD compared with that from healthy controls. The notion that Th17 cells
are not responsible for the tissue damage in this setting was reinforced by
immunohistochemical analysis of skin biopsies showing that very few T cells
from GVHD lesions produced IL-17 or IL-22. Finally, the authors demon-
strated that in patients with acute GVHD, there was actually a higher percent-
age of IFN-γ
+
CD4
+
Th1 cells in the skin compared with healthy donor skin,
and infiltrating T cells expressed CCR5, a Th1-associated chemokine recep-
tor. Thus, in both studies, there was no evidence of an increased percentage
or number of Th17 cells in acute GVHD of the skin.
286
In contrast to these reports, there has been one study that has reported an
augmented Th17 response in patients with GVHD
[104]
. In this publication,
the authors found a significant increase in IL-17-producing CD4
+
T cells in
patients with acute GVHD compared with healthy donors or patients with-
out GVHD. Furthermore, in patients with active chronic GVHD, but not in
patients with inactive chronic GVHD, a significant increase in Th17 cells
was observed. Of note, there was an increased population of IFN-γ and IL-
17-coexpressing Th17 cells, which is an observation made in several ani-
mal studies
[69]
. Plasma IL-17 levels were also significantly increased in
patients with either acute or active chronic GVHD compared with healthy
donors. Interestingly, there was a reciprocal relationship between Th17 cells
and Tregs. In samples from patients with active GVHD, high levels of Th17
cells but low levels of Treg cells were observed. Conversely, the inactive
phase of the disease was associated with an enhanced frequency of Treg
cells but a decreased frequency of Th17 cells. The most interesting aspect
of the study was the observation that T cells that coexpressed IFN-γ and
IL-17 were detected in skin lesions of patients with active chronic GVHD,
whereas these cells were absent in normal skin or skin from patients with
inactive chronic GVHD. Thus, these results are supportive of the premise
that Th17 cells may play a role in some of the cutaneous manifestations of
chronic GVHD.
Role of IL-17 and IL-23R polymorphisms in GVHD
HLA matching between donor and recipient is the major genetic deter-
minant of clinical outcome after allogeneic hematopoietic stem cell
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