Mechanisms of induction of tolerance to organ allografts.

The long-term acceptance of organ allografts can be induced in numerous rodent and some preclinical outbred models. Induction methods can use donor alloantigen in various forms, including spontaneous acceptance of grafts such as livers, to deviate the immune response so a subsequent graft will be accepted. Establishment of lymphohemopoietic chimerism is not essential. Short-term immunosuppressive treatments that prevent acute rejection can also induce tolerance. These include nonspecific immunosuppressive drugs and immunotherapy that blocks cell surface molecular interactions or cytokine function. There is variation in the effect of these protocols on different strain combinations that may be due to innate differences in the cell subpopulations and cytokines activated in the hosts. Th1 cytokines, although important in the mediation of rejection, are also required for induction of tolerance. Th2 cytokines may facilitate tolerance induction but are not essential. The tolerant state takes weeks to fully mature after exposure to alloantigen. Tolerance is associated with a loss or change in dendritic cells and the development of suppressor cells, which in all cases include CD4+ T cells. In the near future precise understanding of the function of these two cell types may allow diagnosis and induction of tolerance in clinical transplantation.