Mechanisms of induction of tolerance to organ allografts

The long-term acceptance of organ allografts can be induced in numerous rod ent and some preclinical outbred models. Induction methods can use donor al loantigen in various forms, including spontaneous acceptance of grafts such as livers, to deviate the immune response so a subsequent graft will be ac cepted. Establishment of lymphohemopoietic chimerism is not essential. Shor t-term immunosuppressive treatments that prevent acute rejection can also i nduce tolerance. These include nonspecific immunosuppressive drugs and immu notherapy that blocks cell surface molecular interactions or cytokine funct ion. There is variation in the effect of these protocols on different strai n combinations that may be due to innate differences in the cell subpopulat ions and cytokines activated in the hosts. Th1 cytokines, although importan t in the mediation of rejection, are also required for induction of toleran ce. Th2 cytokines may facilitate tolerance induction but are not essential. The tolerant state takes weeks to fully mature after exposure to alloantig en. Tolerance is associated with a loss or change in dendritic cells and th e 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 transplan tation.