The blockade of T-cell co-stimulation as a therapeutic stratagem for immunosuppression: Focus on belatacept

Renaud Snanoudj^1,2, Carlos Frangié^1,2, Benjamin Deroure¹, Hélène François^1,2, Caroline Créput^1,2, Séverine Beaudreuil¹, Antoine Dürrbach^1,2, Bernard Charpentier^1,2

¹Service de Néphrologie et Transplantation Rénale, Hôpital du Kremlin Bicêtre, Assistance Publique Hôpitaux de Paris; Le Kremlin-Bicêtre; France; ²INSERM UMR542, Université Paris-Sud, Villejuif, France

Abstract: The development of immunosuppressive drugs has in recent years been focused on prevention of acute rejection. This has led to an increase in one-year allograft survival. However, these drugs have non-immune effects which contribute to the high incidence of late graft loss, as a consequence of chronic allograft nephropathy, and the death of patients. As an immune-specific alternative to conventional immunosuppressants, new biotechnology tools have been developed; they target the costimulation signal of T-cell activation, particularly by the “classical” B7/CD28 and CD40/CD40L pathways. Here, we review the limitations of current immunosuppressive protocols, the benefits of classical B7/CD28 costimulation blockade, and the first large-scale clinical application of this strategy to human transplantation with belatacept. We will also consider novel costimulatory molecules of the B7/CD28 and TNF/TNF-R families, which appear to be important for the functions of memory and effector T-cells.

Keywords: kidney transplantation, immunosuppressants, costimulation, belatacept, chronic allograft nephropathy, fusion protein