RNAi-mediated silencing of CD40 prevents leukocyte adhesion on CD154-activated endothelial cells.
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.
Pluvinet
Raquel
R
Medical and Molecular Genetics Center, Institut de Recerca Oncològica (IRO), Hospital Duran i Reynals, Gran Via s/n km 2.7, 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
Pétriz
Jordi
J
Torras
Joan
J
Herrero-Fresneda
Inmaculada
I
Cruzado
Josep M
JM
Grinyó
Josep M
JM
Aran
Josep M
JM
D000893:Anti-Inflammatory Agents; D019013:CD40 Antigens / Q000235:genetics* / Q000502:physiology; D023201:CD40 Ligand; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D042783:Endothelial Cells / Q000166:cytology* / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D007962:Leukocytes / Q000166:cytology*; D034741:RNA, Small Interfering / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D019013:CD40 Antigens; D034741:RNA, Small Interfering; D023201:CD40 Ligand