Revisiting liver transplant immunology: from the concept of immune engagement to the dualistic pathway paradigm.

Ever since the demonstration that allografts are rejected through immune reactions of the host, clinical therapies for organ allografts have relied on immune suppression to prevent these destructive events. A growing body of clinical and experimental data suggests that allografts elicit multiple, interactive immune responses. The result is not inevitably graft rejection, and "spontaneous" acceptance of fully allogeneic liver grafts occurs in rodents without immunosuppression. A spectrum of results range from spontaneous acceptance without immunosuppression to rejection with immunosuppression. The "dualistic pathway paradigm" aims to reconcile apparently conflicting observations in liver transplantation and proposes that: (1) immune engagement between the host and the allograft is instrumental in both rejection and acceptance; (2) there exist in all mammalian species congruent interactive pathways of immune activation whereby the fate of the allograft is determined by the quantitative results of these interactions; (3) the dualistic effect of immunosuppressive drugs on pathways of immune activation, conferring the capacity for favorable or unfavorable graft outcome should be investigated in experimental models in which organ allografts are spontaneously accepted. In conclusion the design of clinical strategies based on this research may contribute to protocols resulting in allograft acceptance without chronic immunosuppression.