A role for fractalkine and its receptor (CX(3)CR1) in cardiac allograft rejection

The hallmark of acute allograft rejection is infiltration of the inflamed g raft by circulating leukocytes. We studied the role of fractalkine (FKN) an d its receptor, CX(3)CR1, in allograft rejection. FKN expression was neglig ible in nonrejecting cardiac isografts but was significantly enhanced in re jecting allografts, At early time points, FKN expression was particularly p rominent on vascular tissues and endothelium, As rejection progressed, FKN expression was further increased, with prominent anti-FKN staining seen aro und vessels and on cardiac myocytes, To determine the capacity of FKN on en dothelial cells to promote leukocyte adhesion, we performed adhesion assays with PBMC and monolayers of TNF-alpha -activated murine endothelial cells under low-shear conditions. Treatment with either anti-FKN or anti-CX(3)CR1 -blocking Ab significantly inhibited PBMC binding, indicating that a large proportion of leukocyte binding to murine endothelium occurs via the FKN an d CX(3)CR1 adhesion receptors. To determine the functional significance of FKN in rejection, we treated cardiac allograft recipients with daily inject ions of anti-CX(3)CR1 Gb, Treatment with the anti-CX(3)CR1 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 rejec tion.