Preclinical bridge to clinical tolerance

This review considers whether protocols for deliberate induction of transplant tolerance to organ allografts will become a clinical reality. Three current nonhuman primate (NHP) preclinical models that seem likely to lead to clinical tolerance are discussed. These are (1) donor bone marrow in combination with antibody, or immunotoxin or irradiation or both; (2) costimulatory blockade with or without donor bone marrow, and (3) immunotoxin-based T-cell depletion combined with deoxyspergualin to block early posttransplant NF-κB-dependent dendritic cell maturation and proinflammatory cytokine responses. Each model can prevent acute allograft rejection, making prevention of chronic rejection the goal for establishing clinical efficacy. It is noteworthy that the first and third strategies have yielded numerous long-term, drug-free tolerant NHP recipients (kidney and islet transplants) who are free of measurable chronic rejection. As these three NHP strategies are refined and critically replicated by collaborating centers, transplant tolerance induction will be poised for clinical application.