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Blood, 1 December 2004, Vol. 104, No. 12, pp. 3642-3646.
Prepublished online as a Blood First Edition Paper on August 17, 2004; DOI 10.1182/blood-2004-03-0817.


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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Brief report

RNAi-mediated silencing of CD40 prevents leukocyte adhesion on CD154-activated endothelial cells

Raquel Pluvinet, Jordi Pétriz, Joan Torras, Inmaculada Herrero-Fresneda, Josep M. Cruzado, Josep M. Grinyó, and Josep M. Aran

From the Medical and Molecular Genetics Center, Institut de Recerca Oncològica (IRO), Hospital Duran i Reynals, L'Hospitalet de Llobregat, Barcelona, Spain; the Servei d'Hemoteràpia i Hemostàsia, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Universitat de Barcelona, Barcelona, Spain; and the Laboratory of Nephrology, Medicine Department, Hospital Universitari de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.

The CD40-CD154 dyad has a central role in the development of immune-inflammatory processes. Therefore, disruption of CD40 signaling has the potential to be therapeutically useful in a number of disease indications, including autoimmune syndromes, atherosclerosis, and allograft rejection. Blocking antibodies to CD154 have been successfully employed in experimental animal models, and recently in clinical trials, to prevent or treat these immunologically induced diseases. However, the thrombotic events observed in some of these studies raise important issues regarding future use of anti-CD154 antibodies in humans. In this study, we demonstrate that a small interfering RNA (siRNA) can effectively reduce the surface expression of the human CD40 costimulatory receptor. Moreover, by rendering endothelial cells unresponsive to CD154+ Jurkat cell–mediated activation through RNA interference, induction of endothelial cell-adhesion molecule expression and leukocyte adhesion is prevented in vitro. Thus, anti-CD40 siRNA may become a safe and effective therapeutic option for interfering with CD40-CD154–mediated acute or chronic immune-inflammatory conditions.


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