Chemokines and graft-versus-host disease - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 402

HCT with CCR1 −/− donor cells significantly reduced systemic and target
organ GVHD severity, and CCR1 expression on both T cells and accessory
cells contributed to GVHD mortality. While significant cytolytic effector
function of CCR1-deficient cells was maintained, T-cell proliferation and
IFN-γ secretion were significantly reduced both in vivo and in vitro when
interactions between CCR1 and CCL5 were blocked [33] . Further support
for the role of CCL3/CCL5:CCR1/CCR5 interactions in the development
of GVHD is provided by recent studies showing that treatment with eva-
sin-1, a CCL3-binding protein, resulted in diminished T-cell infiltration in
the GI tract and liver [66] . These finding were associated with decreased
systemic CCL5 and IFN-γ levels and GVHD-related mortality and pres-
ervation of GVT effects (see also Chemokines and Leukocyte Trafficking
after Allogeneic HCT).

MONOCYTE RECRUITMENT AND CCR2:CCL2 INTERACTIONS

Following their recruitment to sites of inflammation, effector T cells can be
restimulated to secrete additional chemokines, which may contribute to
the recruitment of monocytes, neutrophils, and additional Th1 cells [13] .
Indeed, donor accessory cells contribute to the pathogenesis of acute GVHD
and are believed to do so via the secretion of soluble inflammatory media-
tors such as TNF-α and IL-1 [8] . CCR2 is highly expressed on monocytes,
DCs, NK cells, and activated T cells of both the Th1 and the Th2 phenotype
but not on naïve T cells, neutrophils, or eosinophils [53] . CCR2 is (1) a major
regulator of induced macrophage trafficking in vivo, (2) critical to the arrest
of rolling monocytes during flow conditions, and (3) a regulator of the gen-
eration of Th1 versus Th2 responses [67,68] . Mice lacking CCR2 develop nor-
mally but exhibit significant defects in monocyte/macrophage recruitment
to sites of inflammation [67] and have diminished IFN-γ response in vivo
and in vitro [69] . CCL2 (MCP-1) is perhaps the best-studied ligand for CCR2
[70] . CCL2 (also murine JE) is a member of the CC chemokine family that has
chemoattractant activity for monocytes, T cells, mast cells, and basophils.
CCL2 is produced by a variety of immune and nonimmune cells, and its
expression is enhanced by inflammatory stimuli such as LPS, TNF-α, IL-1,
and IL-4 [4,17] . In addition to its chemotactic activity, CCL2 can modulate
innate immunity via effects on macrophage function and adaptive immu-
nity via regulation of effector T-cell differentiation and function [13] .

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A role for CCR2:CCL2 receptor:ligand interactions in alloimmune reactions
has been demonstrated by several studies (reviewed in [18] ). Upregulation
of CCL2 expression has been observed during renal allograft rejection in
humans and in mouse cardiac, skin, and orthotopic tracheal transplant
models. In response to early ischemia-reperfusion injury in heart and
skin transplant models, an increase in CCL2 and CXCL2 (MIP-2 and KC)
accompanies a mixed inflammatory infiltrate of monocytes and neutro-
phils. Increased CCL2 expression persists and is ultimately associated with
the appearance of ligands for both CXCR3 and CCR5 as allograft rejection
progresses [17] . In this context, the use of CCR2 −/− recipients increases car-
diac graft survival time by 100% in the absence of additional immunosup-
pression. A critical role for receptor:ligand interactions between CCR2 and
CCL2 has also been reported in the pathogenesis of bronchiolitis obliterans
(BrOb). Elevated bronchoalveolar lavage (BAL) fluid levels of biologically