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Current immunosuppression regimens are toxic to transplant recipients and, in many cases, acute rejection episodes occur because of escape of donor-reactive lymphocytes from the immunosuppression. T cells are the mediators of acute, cell-mediated graft damage and are hypothesized to use the CXCR3 chemokine axis for migration into the allograft. This study investigates the effect of CXCR3 blockade using a nonpeptide, small molecule inhibitor, AMG1237845, in murine cardiac allograft survival.C57BL/6 (H-2b) mice received vascularized cardiac allografts from A/J (H-2a) donors and were treated with the CXCR3 antagonist. Histologic and flow cytometric analyses were used to measure infiltration of leukocytes, and quantitative reverse-transcriptase polymerase chain reaction and interferon-γ ELISPOT assays were used to measure donor-specific reactivity.CXCR3 antagonism modestly prolonged allograft survival compared with vehicle treatment, but at time-matched intervals posttransplant, neutrophil, CD8+, and CD4+ T cell infiltration was indistinguishable. Although proliferation of donor-reactive naïve T cells was unaffected by CXCR3 antagonism, the frequency of interferon-γ-producing cells in the recipient spleen was significantly reduced by AMG1237845 treatment. CXCR3 blockade for 30 days synergized with short-term, low-dose anti-CD154 monoclonal antibodies to prolong survival past 50 days in 75% of grafts and past 80 days in 25% of the cases.These results indicate that in synergy with co-stimulation blockade, CXCR3 is a viable therapeutic target to prevent acute graft rejection.