Mechanisms of tolerance induction: blockade of co-stimulation.
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.
Sebille
F
F
Institut National de la Santé et de la Recherche Médicale, Institut de Transplantation et de Recherche en Transplantation, Chu-Hotel Dieu, 30 Boulevard Jean Monnet, 44093 Nantes Cedex 01, France.
Vanhove
B
B
Soulillou
J P
JP
D000818:Animals; D018122:B7-1 Antigen / Q000276:immunology*; D018801:CD2 Antigens / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D006801:Humans; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology*; D023001:Transplantation Tolerance / Q000276:immunology*
D018122:B7-1 Antigen; D018801:CD2 Antigens; D018106:CD28 Antigens; D019013:CD40 Antigens; D016169:Lymphocyte Function-Associated Antigen-1; D023201:CD40 Ligand