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the recruitment of T cells, monocytes, and neutrophils to target tissues dur-
ing the development of GVHD.
T-CELL EFFECTORS
Once activated, allospecific T-cell clones differentiate and subsequently
travel to GVHD target tissue where they contribute to target tissue injury
and facilitate the recruitment of other cellular effectors. Activated T cells are
characterized by their responsiveness to numerous inflammatory chemo-
kines that are produced at the site of tissue injury and by the correspond-
ing cell surface receptors that are upregulated on these cells in secondary
lymphoid organs or during their migration through an inflammatory envi-
ronment. In vitro studies have demonstrated that receptor expression and
responsiveness are very dependent on IL-2, a cytokine that links the acqui-
sition of migratory capacity to T-cell expansion [38] .
The cell surface expression of CXCR3 and CCR5 identifies a subset of T cells
with the capacity to migrate to sites of injury; both are expressed on a high
proportion of T cells associated within inflammatory lesions compared to
T cells in the peripheral blood or lymph node [39,40] . CXCR3 + and CCR5 + T
cells in the blood generally have a phenotype consistent with previous acti-
vation: β1-integrin hi , CD45RO + , and CD45RA low . Similarly, after alloantigen
stimulation in a mixed leukocyte culture (MLC), CD4 + T cells with an acti-
vated phenotype (CD45RO + , CD45RA , CD69 + , CD25 + ) upregulate CXCR3
[41] . Although the expression of CCR5 and CXCR3 is believed to be more
of a marker for Th1 cells [39] , they can be expressed on both Th1 and Th2
effectors. By contrast, Th2 cells preferentially express CCR3, CCR4, and/or
CCR8. Immunohistochemical staining of inflamed tissues from patients
with rheumatoid arthritis and multiple sclerosis (two Th1 diseases) demon-
strated that virtually all infiltrating cells express CCR5 and CXCR3 [42] . Since
the prevailing view is that effector T cells contributing to tissue damage fol-
lowing allogeneic HCT are primarily of the Th1 phenotype, the potential
contributions of CXCR3 and CCR5 expression to the development of GVHD
will be discussed in detail.
403
Receptor:ligand interactions involving CXCR3 and CXCL9, CXCL10 and CXCL11
CXCR3 is highly expressed on activated T cells and is believed to be critical
to the recruitment of these cells to sites of inflammation and allograft rejec-
tion [15,39] . It is also found on a proportion of circulating NK cells but not
on monocytes, neutrophils, or resting T cells [39] . CXCR3 mediates chemo-
taxis in response to its ligands CXCL9 (Mig), CXCL10 (IP-10), and CXCL11
(I-TAC) and is not known to recognize other CXC or CC chemokines. Like-
wise, CXCL9, 10, and 11 are potent chemoattractants for activated T cells
and can be produced by endothelium, macrophages, and neutrophils, and,
as their names imply, their expression is enhanced by IFN-γ [43] .
A role for CXCR3 and its ligands in alloimmune activation has been dem-
onstrated in models of solid organ transplantation (reviewed in [18] ). The
administration of CXCL9 antibodies reduces cellular infiltration and pro-
longs survival of MHC class II, but not class I, disparate skin grafts. Inter-
estingly, the direct administration of rCXCL9 can overcome the inability of
alloantigen-primed T cells from IFN-γ −/− recipients to reject a skin graft. The
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