Biology Reference
In-Depth Information
expression of CXCR3 and its ligands also contributes to the development of
cardiac allograft vasculopathy and rejection in both clinical and preclinical
studies. In a fully mismatched mouse model, progressive intragraft mRNA
expression of CXCR3, along with CXCL9, 10, and 11, was observed prior to
end-stage rejection. Prolonged graft survival observed in mice deficient
in CXCR3 was associated with a decreased number of infiltrating CD4
+
,
CD8
+
cells, macrophages, and CD25
+
(IL-2R
+
) cells. A subsequent study
using polyclonal antibodies determined that CXCL9, rather than CXCL10,
is the dominant factor responsible for the rejection of cardiac allografts.
Anti-CXCL9 antibodies impaired the recruitment, but not the priming, of
CXCR3
+
T cells during rejection. Of particular interest, CXCL9 was produced
by the allograft endothelium and also by infiltrating macrophage and neu-
trophils, suggesting a possible contribution of these accessory cells to T-cell
recruitment during acute rejection. Experimental data directly correlated
with clinical findings; expression of CXCR3 and its ligands is increased in
endomyocardial biopsies during acute rejection and CXCR3 mRNA is local-
ized to the endothelium and infiltrating mononuclear cells.
Interactions involving CXCR3 and its ligands (CXCL9, 10, and 11) also con-
tribute to the infiltration of donor T cells into GVHD tissues after allogeneic
HCT. In one study, CXCR3 expression is increased on CD8
+
cells infiltrat-
ing the liver 1 week after the transfer of allogeneic spleen cells
[44]
. Sub-
sequently, mice receiving allogeneic HCT from minor histocompatibility
antigen disparate, CXCR3
−/−
donors had significantly fewer CD8
+
lympho-
cytes in the lamina propria and intraepithelial compartments compared
to animals receiving CXCR3
+/+
cells. This translated to improved survival
and lower clinical GVHD scores compared to allogeneic controls
[45]
. The
expression of CXCL9 and CXCL10 is also increased in the lung after allo-
geneic HCT
[46,47]
and directly correlates with the recruitment of CXCR3-
expressing CD8
+
T cells by day 7 after transplant
[47]
. Similar findings were
observed in the lungs of allograft recipients during rejection episodes
[48]
.
Strategies to block CXCR3 receptor:ligand interactions including the
in vivo
neutralization of CXCL9 or CXCL10, the infusion of CXCR3
−/−
donor leu-
kocytes, and the administration of small-molecule antagonists to CXCR3
resulted in reduced lung inflammation and improved survival following
allogeneic HCT recipients
[45,47,49]
. From a clinical perspective, a study
from the United Kingdom evaluated chemokine expression in serum and
skin biopsies from 34 allogeneic HCT recipients
[50]
. In all patients, detect-
able levels of the proteins for CXCL9-11, CCL2, and CCL5 were found in the
serum, with statistically significant increased expression of CCL5 (through
day 35) and CXCL10 (through day 100) in patients who developed GVHD.
Elevated serum levels of CXCL10 correlated with intralesion expression of
this chemokine along with positive staining for CXCR3 within dermal infil-
trates
[50]
. Collectively, these data suggest that the expression of CXCR3 on
infiltrating CD8
+
lymphocytes may contribute to both target tissue and sys-
temic GVHD.
404
Receptor:ligand interactions involving CCR1, CCR5, CCL3, and CCL5
Many groups have studied the expression patterns of CCR1 and CCR5
and their ligands CCL3 (MIP-1α) and CCL5 (RANTES)
[13,51]
. CCL3 and
CCL5 can be produced by a number of activated cell types including
Search WWH ::
Custom Search