Toward tolerance: lessons learned from liver transplantation

*Define the various concepts of transplantation tolerance: Immunologically: unresponsiveness to donor antigens Clinically: ability to discontinue nonspecific immunosuppression Outcome-based: ability to prevent long-term immunologically mediated graft loss (i.e., chronic rejection). *Understand the various possible mechanism(s) involved in developing transplantation tolerance: Central tolerance: clonal deletion Peripheral tolerance: Blocking antibodies Cytokine imbalance Clonal T-cell anergy Active regulation of T- and B-cell proliferation. *Methods to achieve transplantation tolerance: Macrochimerism: recipient cytoablation and donor reconstitution Microchimerism: bone marrow augmentation, growth factors Intrathymic inoculation: central tolerance? T-cell costimulatory blockade: induction of T-cell anergy. *Limitations of achieving transplantation tolerance: No markers to define tolerance Poor understanding of acute and chronic rejection mechanisms (e.g., direct v indirect antigen presentation, high- v low-affinity T cells for alloantigen) What cells are involved in the development of tolerance? How stable is clinical tolerance: are the dynamics influenced by nontransplant factors (e.g., antigenic stimulation by viral factors)? Need for a two-pronged approach: nonspecific phase followed by specific phase?