Biology Reference
In-Depth Information
Chemokines and leukocyte trafficking after
allogeneic HCT
Hematopoietic stem cell homing
The success of HCT as a clinical therapeutic option is predicated upon
the ability of the transplanted donor stem cells to home to the bone mar-
row microenvironment and reestablish the hematopoietic and peripheral
immune elements of the recipient. Homing is a process that involves the
migration of hematopoietic stem cells (HSCs) through the bone marrow
vascular endothelium and subsequent localization into the appropriate
“niche.” The latter is facilitated by adhesive interactions with the bone mar-
row stroma and extracellular matrix. Although some of the components
responsible for stem cell homing have been elucidated, many aspects of the
process remain to be determined.
Interactions between CXCR4 and its primary ligand, CXCL12 (stromal cell-
derived factor-1α—SDF-1α), are critical to HSC homing and engraftment
(reviewed in
[18]
). CXCR4 is expressed on HSCs and CXCL12 is a chemoat-
tractant for HSCs
in vitro.
Clinical studies have highlighted the efficacy
of an antagonist of CXCR4 to enhance the mobilization of HSCs into the
peripheral blood for collection when used in combination with granulo-
cyte colony-stimulating factor
[19]
. CXCL12 upregulates surface adhesion
molecules, which are critical to the arrest and transmigration of CD34
+
cells through vascular endothelium
[20]
. Hematopoiesis in animals lack-
ing either CXCL12 or CXCR4 fails to transition successfully from fetal liver
to bone marrow, resulting in death within the perinatal period
[21]
. Adams
and colleagues found that co-infused CD8
+
T cells augment CD34
+
cell hom-
ing to the bone marrow by altering the phosphotyrosine-mediated signal-
ing of CD34
+
cells in response to CXCL12
[22]
. In addition, cleavage of the
N terminus region of CXCL12 by the membrane-bound peptidase CD26/
dipeptidylpeptidase IV may represent a novel regulatory mechanism in the
migration, homing, and mobilization of HSCs
[23]
.
400
The role of CXCR4:CXCL12 interactions in HSC homing has been chal-
lenged by data demonstrating that CXCR4
−/−
fetal liver cells can home and
engraft in the bone marrow compartment of wild-type mice
[24]
and spe-
cific inhibitors of CXCR4 function do not significantly disrupt HSC engraft-
ment
[25]
. These findings suggest that CXCR4:CXCL12 interactions may
act in conjunction with other receptor:ligand interactions, including those
with CCR9 and CCR3, to facilitate HSC homing and engraftment, and such
alternative pathways remain under investigation
[26]
.
Once HSCs have successfully homed to the bone marrow microenviron-
ment, they must begin the processes of self-renewal and lineage-specific
repopulation within the host. As hematopoietic precursors mature and
become more restricted in proliferative and lineage potential, there is a
differential expression of chemokine receptors on the cell surface. In this
context, CXCR4 expression has been shown to regulate the retention of gran-
ulocyte precursors in the bone marrow
[24]
. The inflammatory processes of
GVHD can suppress myelopoiesis directly through production of inflam-
matory cytokines and through induction of chemokines, many of which
can inhibit proliferation of myeloid progenitors. Furthermore, although
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