Expression of the chemokine receptor CXCR3 and its ligand IP-10 during human cardiac allograft rejection

Background-Chemokines play an essential role in regulating the infiltration of leukocytes into allografts in experimental models. Little is known of t heir expression or function after human cardiac transplantation. Methods and Results-We analyzed 169 sequential human endomyocardial biopsie s by immunocytochemistry for infiltration by CD3(+) T cells and the express ion of the chemokine receptors CCR1, CCR3, CCR5, and CXCR3. In both cross-s ectional and longitudinal analyses, the expression of each of the chemokine receptors correlated with the degree of CD3(+) T-cell infiltration. In par ticular, the expression of CXCR3 was temporally and spatially associated wi th CD3(+) T-cell infiltrates and correlated with the histopathological diag nosis of acute rejection (OR, 11.73 and 4.05, respectively; P <0.001). Of 7 patients followed up longitudinally for 1 year, 4 with consecutive biopsie s developed intimal thickening by intravascular ultrasound. In these patien ts, there was a trend for persistent expression of CD3- and CXCR3-expressin g infiltrates in the later part of the first posttransplant year. The chemo kines eotaxin, IP-10, lymphotactin, MCP-1, Mig, RANTES, and SDF-1 were exam ined in an additional 35 biopsies by RT-PCR. Eotaxin, lymphotactin, MCP-1, mg, and SDF-1 were present in both normal and rejecting biopsies. However, the CXCR3 ligand IP-10, which was rarely expressed in normal biopsies, was markedly induced in acute rejection (OR, 19.43; P=0.01). Conclusions-The presence of CXCR3(+) T cells and the CXCR3 ligand IP-10 wit hin endomyocardial biopsies is strongly associated with acute rejection. Th e CXCR3-IP-10 interaction warrants consideration as a therapeutic target in the management of cardiac allograft recipients.