Mechanisms of tolerance induction: blockade of co–stimulation

Abstract

Induction of tolerance to transplantation antigens is believed to be a promising way to achieve long–term allograft survival without a deleterious immunosuppressive regimen. T–cell activation, which is an essential feature of graft rejection, requires a first signal provided by T–cell receptor (TCR) ligation and a second signal provided by engagement of co–stimulatory molecules with their respective ligands on antigen–presenting cells. The coordinated triggering of these two independent signalling systems ensures the full T–cell activation, including proliferation and acquisition of effector function. TCR occupancy in the absence of co–stimulatory signals leads to a sustained loss of antigen responsiveness called clonal anergy, which could be of major importance in transplantation. In vivo , co–stimulation blockade was indeed shown to allow for long–term allograft survival in several transplantation models. However, the current continuous identification of new co–stimulatory molecules suggests that a functional redundancy of the system exists and that tolerance to transplantation antigens might be achieved more easily through the combined blockade of two or several co–stimulatory signals. In this review, we analyse the biological effects of the disruption of some co–stimulation pathways in vitro and in vivo and discuss their potential interest for tolerance induction.