The molecular mechanisms of veto mediated regulation of alloresponsiveness

Transplantation tolerance, as defined by the specific acceptance of allogeneic tissue without chronic immunosuppression, can be induced in adults by a variety of methods. One method that is close to clinical implementation involves transient peritransplant depletion of host T cells followed by intravenous administration of a low dose of donor bone marrow cells (BMC). Current evidence suggests that BMC play an active role in tolerance induction by establishing residence in the host and effecting deletion of graft reactive T cells. This activity, in which the BMC inactivate T cells that recognize them, has been called the 'veto effect,' and cells that mediate such activity have been called 'veto cells.' The specificity of veto activity is conferred by the T cell receptor of the donor reactive T cells that are to be deleted. Other molecules that have been directly implicated in the mechanism of deletion of graft reactive T cells by BMC include the CD8 accessory molecule, major histocompatibility class I gene products, CD95/CD95 ligand (Fas/Fas ligand), and transforming growth factor-β. These molecules react with their respective ligands by distinct, nonexclusive pathways among which the relative contribution to the deletion of graft reactive T cells may depend on the relative abundance of different cellular subpopulations capable of mediating veto activity.