Regulation of immune reactivity and tolerance by antigen migration and localization: with particular reference to allo- and xenotransplantation.

THE SPECIFIC immunologic non-reactivity to allografts that was first produced in fetal or neonatal mice by Billingham, Brent, and Medawar,l and. ultimately, in human bone marrow recipients25 has remained enigmatic for nearly a half century. Without first understanding this "acquired tolerance," and. especially, the "acceptance" of organ allografts it is folly to dream of a future that includes xenotransplantation. Beginning in 1992.6 we have developed an explanation for successful transplantation of allografts that, if valid, could guide investigators directly to the objective of clinical xenotransplantation. A central tenet of our proposal is that immune reactivity or non-reactivity (tolerance) to transplanted tissues and organs. to microorganisms, and to all other antigens (including self), is governed by the migration and localization of the antigen.7 Evidence supporting the latter conclusion has been obtained from investigations of the previously unsuspected chimerism that occurs after organ transplantation6•8 .9 and from observations following experimental and clinical infections. 10-12