Transplant tolerance: models, concepts and facts

Despite extensive research, our understanding of immunological tolerance to self-antigens is incomplete, and the goal of achieving tolerance to allogeneic transplanted tissue remains elusive. Currently, it is generally believed that the blockade of T cell co-stimulation offers considerable potential for achieving tolerance in the clinical setting. However, the recent finding that CD154-specific antibody may act through the depletion of activated T cells rather than co-stimulation blockade alone highlights the need for a re-evaluation of published data and the role of co-stimulation blockade in transplant tolerance. Activated T cells are programmed to die unless they receive sufficient survival signals in the form of inflammatory and lymphotropic cytokines produced by activated antigen-presenting cells or the T cells themselves. In conditions where the threshold for surviving activation is not reached, for example when a small number of responder T cells are activated in the absence of substantial injury or inflammation, the ensuing death of all activated T cells can result in deletional tolerance. Therefore, we propose that tolerance represents a failure of T cells to survive activation and develop into memory cells. This concept is likely to apply in the transplant setting, where the strength of the alloresponse depends on both the number/phenotype of the recipients’ alloreactive T cells and immunogenicity of the transplanted tissue. Hence, in some rodent donor–recipient strain combinations that instigate a weak alloresponse, many treatments that only modestly decrease the alloresponse can achieve tolerance. In contrast, clinical transplantation is characterised by a strong alloresponse and highly immunogenic allografts, and thus, most treatments fail to control allograft rejection, and tolerance is difficult to achieve.