Time, space and contextual models of the immunity tolerance decision: bridging the geographical divide of Zinkernagel and Hengartner's 'Credo 2004'.

In Credo 2004, Zinkernagel and Hengartner (Z&H) have continued their challenge to the immunological community to reconsider assumptions regarding the most fundamental aspects of adaptive immunity. They have appropriately championed the role of persistent, widely distributed antigen in tolerance induction, parameters that do not figure prominently in most other models. The global theory of immunity they have developed is predominantly based on observations from studies with viruses and tumours. I suggest here that a more successful approach to generating a theory of the default rules of immunity can be obtained through the study of immunity versus tolerance in the setting of transplantation. Transplantation studies lack the confounding variable of competing evolution present in responses to specific infectious agents and tumours and, therefore, more clearly elucidate default rules of immunity. The geographical model in Credo 2004, primarily a one-signal model regulated by antigen, is contrasted with (1) Cohn's time-based two-signal model and (2) a development-context model that postulates distinct central and peripheral tolerance mechanisms.