Mechanisms of tolerance induction: blockade of co-stimulation

Induction of tolerance to transplantation antigens is believed to be a prom ising way to achieve long-term allograft survival without a deleterious imm unosuppressive regimen. T-cell activation, which is an essential feature of graft I ejection, requires a first signal provided by T-cell receptor (TCR ) ligation and a second signal provided by engagement of co-stimulatory mol ecules with their respective ligands on antigen-presenting cells. The coord inated triggering of these two independent signalling systems ensures the f ull T-cell activation, including proliferation and acquisition of effector function. TCR occupancy in the absence of co-stimulator signals leads to a sustained loss of antigen responsiveness called clonal anergy which could b e of major importance in transplantation. In vivo, co stimulation blockade was indeed shown to allow for long-term allograft survival in several trans plantation 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 achieve ed m ore easily through the combined blockade of two or several co-stimulatory s ignals. 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 in terest for tolerance induction.