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the development of autoimmune manifestations as described by de Jager
et al.
[87]
. However, these data would appear to indicate that the short-term
blockade of CCR7 function in the early transplant period as a means for
attenuating the ability of donor Tcons to induce GVHD would be tolerable
from the perspective of the donor Treg function.
Several studies have also examined the impact of inflammatory chemokine
receptors on donor Treg function after HCT. The first
[88]
made use of donor
Tregs knocked out at the CCR5 locus, a chemokine receptor that has been
implicated to varying degrees in the trafficking of Tcons into the recipient
liver and skin
[44,60,61]
. CCR5
−/−
Tregs accumulated within host lymphoid
tissue to a degree that initially approximated WT Tregs. However, by trans-
plant day +10, fewer CCR5
−/−
Tregs were noted within peripheral GVHD tar-
get organs, including the lung and, in particular, the liver. This resulted in
increased GVHD scores in those mice given CCR5
−/−
Tregs and ultimately a
higher mortality rate. Collectively, these results indicated that CCR5 plays
an important role in the beneficial
in vivo
properties of donor Tregs follow-
ing HCT. More generally, these data illustrated that the induction of inflam-
matory chemokine receptor expression during early Treg activation within
lymphoid tissue is crucial for their subsequent migration into peripheral
organs. Furthermore, it would appear that a donor Treg presence within
peripheral GVHD target organs is required for optimal GVHD protection
(see below) and that the early inhibition of donor Tcon expansion within
host lymphoid tissue by donor Tregs is, by itself, insufficient.
411
Varona et al. examined the influence of CC-chemokine receptor 6 (CCR6)
on the ability of donor Tregs to prevent GVHD
[89]
. Naïve CD4
+
CD45
high
T cells from CD1 mice (H-2
d
) were administered to nonirradiated, MHC
minor antigen-mismatched CB17/SCID mice (H-2
d
), with or without regu-
latory T cells from either WT or CCR6
−/−
donors. Recipients of naïve CD4
+
T cells alone went on to develop a wasting syndrome characterized by skin
inflammation, diarrhea, and weight loss and significant mortality by day
+80. When WT donor Trems, defined by the authors as those cells exhib-
iting a CD4
+
CD45RB
low
cell surface phenotype, were coadministered with
the naïve CD4
+
T cells, however, recipient GVHD was greatly reduced,
with 80% of the mice surviving to the end of the study period. CCR6
−/−
CD4
+
CD45RB
low
cells, conversely, were much less effective at reducing host
inflammation, leading the authors to conclude that CCR6 is critical for reg-
ulatory T-cell function. While no Treg
in vivo
trafficking studies were per-
formed, the authors hypothesized that CCR6, like CCR5, may facilitate Treg
function
in vivo
by allowing for activated Treg trafficking into peripheral
target organs.
Hasegawa and colleagues exploited the inflammatory chemokine envi-
ronment present in GVHD target tissues to investigate whether a strat-
egy to optimize the delivery of Tregs would enhance the effectiveness of
these cells in modulating the severity of GVHD
[90]
. Using a lethally irra-
diated parent into F1 system, the investigators found that donor-derived
CD4
+
CD25
+
FOXP3
+
cells transfected with a retroviral vector expressing
CXCR3 demonstrated
(1)
enhanced migration capacity to target organs
expressing CXCL9, 10, and 11;
(2)
prolonged localization in these inflamed
tissues; and
(3)
superior suppressor activity compared to transfected Treg
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