Published Online
on February 2, 2004

A more recent version of this article appeared on February 24, 2004

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Submitted on October 3, 2003
Revised on October 17, 2003
Accepted on October 21, 2003

Combined Blockade of the Chemokine Receptors CCR1 and CCR5 Attenuates Chronic Rejection

James J. Yun MD, PhD, David Whiting MD, Michael P. Fischbein MD, PhD, Anamika Banerji BS, Yoshihito Irie MD, Daniel Stein BS, Michael C. Fishbein MD, Amanda E.I. Proudfoot PhD, Hillel Laks MD, Judith A. Berliner PhD, and Abbas Ardehali MD^*

From the Department of Surgery, Division of Cardiothoracic Surgery (J.J.Y., M.P.F., A.B., Y.I., D.S., H.L., A.A.) and Department of Pathology and Laboratory Medicine (J.J.Y., M.C.F., J.A.B.), University of California at Los Angeles, Los Angeles, Calif; Greater Los Angeles Veterans Administration Healthcare System (J.J.Y., A.A.), Los Angeles, Calif; and Serono Pharmaceutical Research Institute (A.E.I.P.), Geneva, Switzerland.

^* To whom correspondence should be addressed. E-mail: aardehali{at}mednet.ucla.edu.

Background--Chemokine-chemokine receptor interaction and the subsequent recruitment of T-lymphocytes to the graft are early events in the development of chronic rejection of transplanted hearts or cardiac allograft vasculopathy (CAV). In this study, we sought to determine whether blockade of chemokine receptors CCR1 and CCR5 with Met-RANTES affects the development of CAV in a murine model.

Methods and Results--B6.CH-2^bm12 strain donor hearts were transplanted heterotopically into wild-type C57BL/6 mice (myosin heavy chain II mismatch). Recipients were treated daily with either Met-RANTES or vehicle starting on postoperative day 4 and were euthanized on postoperative days 24 and 56. We found that Met-RANTES significantly reduced intimal thickening in this model of chronic rejection and that Met-RANTES markedly decreased the infiltration of CD4 and CD8 T lymphocytes and MOMA-2⁺ monocytes/macrophages into transplanted hearts. Met-RANTES also suppressed the ex vivo and in vitro proliferative responses of recipient splenocytes to donor antigens. Finally, Met-RANTES treatment was associated with a marked reduction in RANTES/CCL5 and monocyte chemoattractant protein-1 gene transcript levels in the donor hearts.

Conclusions--Antagonism of the chemokine receptors CCR1 and CCR5 with Met-RANTES attenuates CAV development in vivo by reducing mononuclear cell recruitment to the transplanted heart, proliferative responses to donor antigens, and intragraft RANTES/CCL5 and monocyte chemoattractant protein-1 gene transcript levels. These findings suggest that chemokine receptors CCR1 and CCR5 play significant roles in the development of chronic rejection and may serve as potential therapeutic targets.

Key words: transplantation • lymphocytes • rejection • chemokine

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