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macrophages, DCs, lymphocytes, and endothelial cells. In particular CCL5
can be expressed by fibroblasts, and epithelial cells within minutes of stim-
ulation and also by T lymphocytes days after activation
[52]
. In addition
to being chemotactic for a variety of cell types including activated T cells,
monocytes, macrophages, NK cells, immature DCs, and neutrophils (via
CCR1 expression in the mouse)
[18]
, CCL5 and CCL3 contribute to antigen-
specific activation of both helper and cytotoxic T cells
[13]
. In mice, CCR5 is
found on both CD4
+
and CD8
+
T cells and NK cells and is weakly detectable
on monocytes
[53]
, whereas CCR1 can be expressed on monocytes, mac-
rophages, and neutrophils
[51]
. CCR5 expression is enhanced during T-cell
activation and differentiation of monocytes to macrophages, which could
explain the colocalization of these cells with effector T cells in the organs
of animals with GVHD. CCR5 is also expressed at high levels on Th1 but
not Th2 lymphocytes
[44]
. CCR5 appears, however, to be a marker of, but is
not essential for, the development of Th1 responses in humans; individuals
homozygous for the Δ32 mutation (and lack CCR5 expression) are healthy
and have adequate numbers of IFN-γ- and IL-2-producing cells
[54]
.
A role for CCR5/CCR1 interactions during allograft rejection has been dem-
onstrated by several studies using preclinical models of lung, kidney, and
cardiac transplant
[15,18]
. Importantly, the functional significance of CCR5
in transplantation immunology was highlighted by examining a cohort of
patients that underwent renal allografting and were genetically deficient
in CCR5; only 1 of 21 CCR5-deficient patients had evidence of transplant
rejection and loss of renal function during follow-up
[55]
. Several investiga-
tors have also studied the role of CCR5 and its ligands in the development of
GVHD. The expression of CCL5 and CCL3 is increased in target tissue after
allogeneic HCT
[46]
, and CCL3 significantly contributes to the recruitment
of CCR5
+
/,CD8
+
T cells into the lung, liver, and spleen in this setting
[44,56]
.
Using strain combinations in which donor and host differ by either class I or
class II MHC antigens, Serody and colleagues
[56]
showed that the majority
of CCL3 produced within the first week in the liver, lung, and spleen was
of donor T cell origin; transfer of splenocytes from CCL3-deficient donors
resulted in a decrease in CCL3 expression in these organs, but not in the GI
tract. Absence of CCL3 in donor cells was associated with decreased recruit-
ment of CD8
+
cells to the liver and lung and resulted in reduced mortality
from GVHD in the MHC class I disparate system
[56]
. These experiments
employed relatively low dose radiation and the transfer of donor spleno-
cytes only. In contrast, HCT with CCL3
−/−
donor cells following myeloabla-
tive conditioning in a fully mismatched strain combination was associated
with an accelerated influx of cytolytic, granzyme B
+
cells into the lungs of
recipient mice at day 3 and resulted in increased mortality from GVHD
[57]
.
405
The initial work by Serody was extended by studies showing that CCR5
+
CD8
+
donor lymphocytes significantly contribute to liver GVHD in an unir-
radiated P → F1 model. In this study, CCR5 expression was increased on
CD8
+
cells infiltrating the liver, and the administration of anti-CCR5 anti-
bodies reduced the severity of hepatic GVHD. Furthermore, CCL3 mRNA
levels were significantly increased in the liver during GVHD, and antibod-
ies to CCL3 reduced the influx of CCR5
+
/CD8
+
donor T cells to this organ
[44]
. CCR5 also contributes to the migration of CD8
+
cells to the subepithe-
lial dome (SED) of gut Peyer's patches, which was initially believed to be
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