Induction of transplantation tolerance and development of lymphomas in mice: Lack of interdependence

Abstract

Neonatal transplantation tolerance was induced in five different H-2-incompatible donor → recipient mouse strain combinations by the iv injection of semiallogeneie (F 1 hybrid) spleen cells. The highest degree of tolerance (expressed by the survival time of the specific test skin allografts) was observed in the (CBA X A)F 1 → CBA combination (~95% permanent tolerance) but some degree of tolerance was achieved in all strain combinations. An increased incidence of malignant lymphoproliferative disorders was observed in all groups of mice which underwent neonatal tolerance induction. The highest incidence of lymphoproliferative malignancies was observed in the (B10 X A)F 1 → A tolerance induction system, in which ~50% of the recipient mice died within 1 year. In further experiments, spleen cells of mice which proved to be permanently tolerant after the neonatal tolerance induction were transferred into syngeneic, normal, adult, ATS-pretreated, allografted recipients; by this method, in ~50% of the recipients permanent “adult” tolerance was achieved. The spleen cells of the “adult” tolerant mice were able to transfer the tolerance to other adult, syngeneic, ATS-pretreated recipients. Even the fourth serial transfer resulted in essentially the same degree of tolerance in the new recipients. We consider the serial transfer a classical instance of “infectious tolerance” based on suppressor mechanisms. However, an increasing number (and malignancy) of lymphomas occurred in the course of the serial transfers and prevented the “indefinite” transfer of tolerance after the fourth occasion. We conclude that both the degree of transplantation tolerance and the high frequency of lymphomas are determined by (immuno)genetic factors but the two phenomena are not interrelated. Thus, successful transplantations do not seem to be necessarily accompanied by an increased incidence of malignancies.