Distinct patterns of chemokine secretion and chemokine receptor
expression shape the inflammatory response in rejecting human liver
transplants
Index
Sarah Goddard, Stefan Hubscher and David Adams
The Liver Research Laboratories, MRC Centre for Immune Regulation,
University of Birmingham UK.
Graft rejection after liver transplantation is associated with
infiltration of the liver by monocytes & lymphocytes and the nature of
this inflammatory response will be determined in part by the local
activity of chemotactic cytokines (chemokines) that attract particular
subsets of effector T cells to the graft. The liver is a source of
chemokines during rejection but little is known about the chemokine
receptors used by leukocytes infiltrating the liver. We studied the
expression of chemokines and chemokine receptors in human liver by
immunohistochemistry and flow cytometry. Normal human liver contained
a light infiltrate of lymphocytes most of which expressed CXCR3 and
some of which stained weakly for CXCR4. Kupffer cells stained weakly
for CCR3. In contrast lymphocytes infiltrating portal tracts during
acute and chronic graft rejection were strongly positive for CXCR3,
CXCR4 & CCR5. This was associated with increased staining for the
respective ligands IP-10 (CXCR3), MIP-1a and MIP-1ß (CCR5), and SDF-1a
and SDF-1ß (CXCR4) in the graft. Moreover these ligands show
distinctive expression patterns with IP-10 expressed on sinusoids,
MIP-1a and ß on vascular endothelium and SDF on parenchymal cells.
Kupffer cells showed a change in phenotype becoming positive for
CXCR1, CXCR2, CXCR4, CCR2 and especially CCR3 and CCR5. In vitro
alloactivation of lymphocytes resulted in increased expression of all
chemokine receptors studied, but with particularly high levels of
CXCR4, CXCR3 and CCR5. Further evidence that these receptors are
functionally important in recruiting lymphocytes to rejecting
allografts is provided by our observation that CXCR3 and CXCR4 are
increased on peripheral blood T cells following liver transplantation.
Thus the patterns of local chemokine expression and the induction of
specific chemokine receptors on alloactivated lymphocytes will
determine the nature of the inflammatory infiltrate in graft
rejection.
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