Published Online
on March 11, 2002

A more recent version of this article appeared on April 2, 2002

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Submitted on November 13, 2002
Revised on January 24, 2002
Accepted on January 28, 2002

Suppression of Murine Cardiac Allograft Arteriopathy by Long-Term Blockade of CD40-CD154 Interactions

Catherine Y. Wang MD, Sean P. Mazer MD, Kanji Minamoto MD, PhD, Shin Takuma MD, Shunichi Homma MD, Michael Yellin MD, Leonard Chess MD, Ali Fard MD, Susan L. Kalled PhD, Mehmet C. Oz MD, and David J. Pinsky MD^*

From Columbia University, College of Physicians and Surgeons, New York, NY (C.Y.W., S.P.M., K.M., S.T., S.H., M.Y., L.C., A.F., M.C.O., D.J.P.), and Biogen Inc, Cambridge, Mass (S.L.K.).

^* To whom correspondence should be addressed. E-mail: djp5{at}columbia.edu.

Background—The interaction between CD40 on antigen-presenting cells and CD40L on T cells is critical in allograft rejection. CD154 blockade suppresses allograft rejection, but the role of this pathway in allograft vasculopathy remains obscure.

Methods and Results—A vascularized murine heterotopic cardiac transplant model was used to test whether perioperative CD154 blockade suppresses allograft vasculopathy or whether long-term CD154 blockade is required to suppress allograft vasculopathy. Perioperative CD154 blockade consisted of MR1 given on days -1, 1, and 3; long-term blockade consisted of MR1 given on days -1, 1, and 3 and continued twice weekly for 8 weeks. Allografts treated with perioperative or long-term CD154 blockade survived indefinitely. Perioperative and long-term treatment with control antibody (Ha4/8) resulted in uniform early rejection. Perioperative CD154 blockade transiently reduced early T-cell and macrophage infiltration in parallel with a transient reduction in endothelial adhesion receptor expression. Although perioperative CD154 blockade prevented allograft failure, it did not reduce allograft vasculopathy; mean neointimal cross-sectional area in perioperative MR1-treated and Ha4/8-treated recipients was 43±7% and 50±12%, respectively (P=NS). In contrast, mean neointimal cross-sectional area in long-term, MR1-treated recipients was 19±3% (P<0.001 versus perioperative MR1). Long-term CD154 blockade also suppressed endothelial E-selectin, P-selectin, and intracellular adhesion molecule-1 expression and improved graft function 3.5-fold versus control (P<0.05).

Conclusions—These data show that perioperative CD154 blockade mitigates acute rejection but long-term CD154 blockade may result in decreased allograft endothelial activation and is required to suppress allograft arteriopathy.

Key words: transplantation • cell adhesion molecules • immunology • rejection

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