New possibilities of therapeutic interventions in transplantation.

Immune tolerance of the graft would allow for long-term graft survival without immunosuppressive drugs. Experimental studies showed that both CD28/B7 and CD40L/CD40 costimulations are critical for allograft rejection and their blockade during transplantation induced a decrease of proliferation of alloreactive T cells and an increase of their death by apoptosis. Blocking B7 costimulation increased rodent allograft survival of kidney, liver and pancreatic islets but this is insufficient weapon in the induction of graft tolerance. The combination of the two treatments has synergistic effects. Additional CD40/CD40L blockade represents a adjunct strategy to prevent graft rejection and it has been reported to induce donor specific peripheral tolerance. This therapy prevented acute cardiac allograft rejection and it markedly prolonged allograft survival of kidney and islets in nonhuman primates. A loss of donor-specific alloreactivity has been demonstrated in these experimental models. Calcineurin inhibitors may antagonize the therapeutic effects of costimulatory blockade which may suggest that T cell receptor signaling may be required for tolerance induction.