Suppression of Acute and Chronic Cardiac Allograft Rejection in Mice by Inhibition of Chemokine Receptor 5 in Combination with Cyclosporine A

Abstract

Inhibition of chemokine receptor 5 (CCR5), a chemokine receptor expressed on activated T cells, is an effective antiviral therapy in patients with HIV infection, but its efficacy in modulating inflammation and immunity is only just beginning to be investigated. In this study we examined the inhibition of CCR5 in combination with the treatment with cyclosporine A in acute and chronic rejection in cardiac transplantation. Eighty fully MHC-mismatched murine cardiac allograft models were randomized to four groups. Recipients in group A were treated with anti-CCR5 mAb and CsA, mice in group B were given anti-CCR5 mAb alone, animals in group C were administered only CsA, and group D were the control group with PBS. Acute and chronic rejection was investigated on day 7 and day 45 post-transplant, respectively. Allografts treated with anti-CCR5 mAb plus CsA showed significantly prolonged survival (44.73 +/- 0.258 d, P < 0.01) compared with PBS-treated group (11.067 +/- 0.707 d). Treatment with anti-CCR5 mAb plus CsA significantly inhibited the progression of CAV. Our findings demonstrated that anti-CCR5 mAb in combination with CsA can prolong the survival of allograft and alleviate both acute and chronic allograft rejection. Thus, combined administration of anti-CCR5 mAb and CsA may become a new therapeutic approach for the prevention of cardiac graft failure that has not been obviated by conventional immunosuppressive agents.