Chemokines and graft-versus-host disease - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 403

active CCL2 correlate with the progression of acute to chronic rejection in
lung transplant recipients [71] . Translational studies using a murine model
of BrOb showed that disrupting CCL2/CCR2 signaling significantly reduces
monocyte/macrophage infiltration and the severity of BrOb.

Mononuclear cell infiltration is a consistent histopathologic finding of
GVHD of the gut, liver, and lung, suggesting that chemokine receptor:ligand
interactions involving CCR2 and perhaps CCR5 facilitate the recruitment of
these cells to target tissues. Enhanced CCL2 expression has been observed
in the liver and lung within the first 2 weeks after allogeneic HCT [9,46] . Pan-
oskaltsis-Mortari and colleagues found that increases in CCL2 levels in the
lung preceded the influx of host macrophages, whereas increases in CCL3
expression accompanied donor T-cell infiltration [46] . These findings were
extended by experiments showing that pulmonary CCL2 and CCR2 mRNA
levels are increased during the development of IPS. Blocking CCR2:CCL2
interactions using either CCR2 −/− donor cells or antibodies to CCL2 results
in decreased lung pathology and a reduction in donor CD8 + lymphocytes
and macrophages in BAL fluid. Importantly, experimental data correlated
with preliminary clinical findings; patients with IPS have elevated levels of
CCL2 in the BAL fluid at the time of diagnosis [72] . Clinically, the presence
of the CCL2-2076 T/T genotype, which correlates with functional effects
in vitro, was found to be associated with decreased overall survival and
increased transplant-related mortality (TRM) in a small subset of 121 HLA-
matched, related-donor, HCT recipients but had no effects on the incidence
or severity of GVHD [73] .

408

NEUTROPHIL RECRUITMENT AND INTERACTIONS BETWEEN CXCR1, CXCR2,
CXCL1 (KC-GRO- α ), AND CXCL2 (MIP-2-GRO- β )

The chemotactic activity of CXC family members is based upon the pres-
ence of a 3-amino-acid “ELR” (glutamic acid-leucine-arginine) motif. ELR +
CXC chemokine ligands are potent chemoattractants for, and activators
of neutrophils, whereas the major targets of non-ELR members are T and
B cells. The two best-studied murine ELR + CXC chemokines, CXCL1 (KC)
and CXCL2 (MIP-2), are the functional homologs of human CXCL8 (IL-8)
and GRO chemokines [74,75] . ELR + CXC chemokines are produced by a
variety of cells, including pulmonary epithelium, vascular endothelium,
neutrophils, and macrophages, and expression is enhanced during inflam-
mation [5] . Two receptors for ELR + CXC chemokines have been identified
in humans: CXCR1 and CXCR2 [76] . Mice, however, express only CXCR2,
which, like the human homolog, is believed to bind nearly all of the ELR +
CXC chemokines [77] . CXCR2 is abundantly expressed on neutrophils and
to a lesser extent on the surface of T cells and monocytes, myeloid precur-
sors, and some nonhematopoietic cells [51] .

A potential role for CXCR2 and its ligands in damage incurred during allo-
immune responses has been suggested by several studies. mRNA and pro-
tein expression of CXCL8 and CINC (the rat homolog of human GRO-α and
murine CXCL1) correlated with rejection in both human heart and human
kidney allografts, and these levels decrease in response to immunosuppres-
sion [18] . Enhanced mRNA expression of CINC and the accumulation of
neutrophils and monocytes in portal areas are also characteristic of acute