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In-Depth Information
rejection of liver transplants
[78]
and both are reduced when hepatic allograft
recipients are treated with FK506. A critical role for CXCL1 has been observed
in the early inflammatory events associated with cardiac allograft rejection.
Increased CXCL1 expression was present early after transplantation, and
administration of a polyclonal anti-CXCL1 antibody early after graft place-
ment attenuated subsequent expression of T-cell chemoattractants, cellular
infiltration into the graft, and graft rejection
[79]
. These findings suggest that
the temporal expression of neutrophil and macrophage chemoattractants
early after transplant is required for optimal recruitment of T cells into the
graft and suggest a link between innate and acquired immunity during the
development of acute rejection. The development of bronchiolitis obliter-
ans syndrome during chronic lung allograft rejection is also associated with
increased neutrophil infiltration into the bronchial walls and bronchoal-
veolar space and with increased BAL fluid levels of CXCL8. In this setting,
CXCL8 may contribute to airway inflammation and subsequent fibroprolif-
eration and obliteration, the hallmarks of this disease process
[80]
. A murine
model of BrOb following allogeneic HSC transplantation (HSCT) has been
lacking until recently, when Panoskaltsis-Mortari et al. demonstrated the
development of obliterative changes in lungs of allogeneic recipients along
with increasing levels of CXCL1 (human CXCL8)
[81]
.
409
The role of neutrophils in the development of GVHD target tissue damage is
poorly understood but is probably related to the effects of microbial prod-
ucts such as LPS and inflammatory cytokine release
[82]
. Unlike lympho-
cytes, neutrophils are incapable of tissue-specific migration or immunologic
memory but can contribute to proteolytic and oxidative tissue damage when
recruited to GVHD target organs. In this light, neutrophils may represent an
important link between innate and adaptive immune responses occurring
after allogeneic HCT. Neutrophilic infiltrates are observed in the development
of acute and chronic GVHD of the lung in both humans and mice and are
also consistently identified in the intestine and liver of animals with GVHD
[82,83]
. Accordingly, a recent, comprehensive biomarker study showed that
CXCL8 was one molecule of a four-marker panel that was predictive for the
incidence and severity of GVHD severity and overall survival
[84]
.
Increased CXCR2 and CXCL1 and CXCL2 mRNA levels have been observed in
the liver (CXCL2) and lung (CXCR2, CXCL1, and CXCL2) after allogeneic HCT
in mice
[9,46,85]
(K. R. Cooke, unpublished observation). In particular, CXCL1
and CXCL2 appear to significantly contribute to the amplification of lung GVHD
seen after the administration of LPS
[82]
. BAL fluid CXCL2 levels increased dra-
matically after LPS challenge, and this response is completely blunted when
animals were treated with rhTNFR:Fc (K. R. Cooke, unpublished observation).
Similar changes were observed in BAL fluid levels of KC, suggesting that neu-
trophil chemoattractant effects of LPS are regulated, at least in part, by TNF-α
and the downstream release of CXCL1 and CXCL2. Despite these associations,
a causal relationship between CXCR2:MIP-2 receptor:ligand interactions, neu-
trophil influx, and GVHD severity remains to be determined.
REGULATORY T CELLS
As is the case with conventional T cells (Tcons), chemokines and their
receptors may influence the
in vivo
function of Tregs. More specifically,
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