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Departments of
*
Pediatrics,
Medicine, and
Pathology, Duke University Medical Center, Durham, NC 27710;
Department of Biology, University of North Carolina, Chapel Hill, NC 27599; and
¶ Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037
The hallmark of acute allograft rejection is infiltration of the
inflamed graft by circulating leukocytes. We studied the role of
fractalkine (FKN) and its receptor, CX3CR1, in allograft
rejection. FKN expression was negligible in nonrejecting cardiac
isografts but was significantly enhanced in rejecting allografts. At
early time points, FKN expression was particularly prominent on
vascular tissues and endothelium. As rejection progressed, FKN
expression was further increased, with prominent anti-FKN staining
seen around vessels and on cardiac myocytes. To determine the capacity
of FKN on endothelial cells to promote leukocyte adhesion, we performed
adhesion assays with PBMC and monolayers of TNF-
-activated murine
endothelial cells under low-shear conditions. Treatment with either
anti-FKN or anti-CX3CR1-blocking Ab significantly
inhibited PBMC binding, indicating that a large proportion of leukocyte
binding to murine endothelium occurs via the FKN and CX3CR1
adhesion receptors. To determine the functional significance of FKN in
rejection, we treated cardiac allograft recipients with daily
injections of anti-CX3CR1 Ab. Treatment with the
anti-CX3CR1 Ab significantly prolonged allograft
survival from 7 ± 1 to 49 ± 30 days (p
< 0.0008). These studies identify a critical role for FKN in the
pathogenesis of acute rejection and suggest that FKN may be a useful
therapeutic target in rejection.
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K. J. Garton, P. J. Gough, C. P. Blobel, G. Murphy, D. R. Greaves, P. J. Dempsey, and E. W. Raines Tumor Necrosis Factor-alpha -converting Enzyme (ADAM17) Mediates the Cleavage and Shedding of Fractalkine (CX3CL1) J. Biol. Chem., October 5, 2001; 276(41): 37993 - 38001. [Abstract] [Full Text] [PDF]
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