Tolerance in baboon kidney transplantation with total lymphoid irradiation(TLI) and anti-CD3/CD4-Idarubicin conjugates

Background. We previously reported the induction of transplantation toleran ce by a modified wide field method of pretransplant total lymphoid irradiat ion (TLI), cumulative dose 800 cGy, given as 80 or 100 cGy fractions twice/ week, in approximately one-third of chacma baboons receiving liver or kidne y allografts (1-4) and in vervet monkeys receiving baboon kidney xenografts (5). In this study, the effects of the administration of brief courses of anti-CD3 or CD4-Idarubicin conjugates on the frequency and predictability o f tolerance induction by TLI were examined. Methods. TLI was administered pretransplant in doses of 800, 600, or 400 cG y. The conjugates were administered either after transplantation in doses o f 0.25 mg/kg body weight, 3 times/week for 2 weeks, or as a single dose of 1.0 mg/kg body weight 24 hr before transplantation. Results. Operational tolerance, defined as normal graft function >1 year af ter transplantation, was obtained in one-half of six baboons receiving the single dose of 1 mg/kg of Idarubicin conjugate pretransplant after 800 cGy of TLI and also in one of four baboons treated with 400 cGy of TLI and a si ngle dose of anti-CD3 conjugate before transplantation. By contrast, admini stration of the conjugated antibodies 3 times/ week for 2 weeks after trans plantation prevented tolerance induction in all animals, providing further evidence for the involvement of active mechanisms, capable of inhibition by immunosuppressive agents, in tolerance induction with TLI, and of relevanc e to our reported clinical experience with TLI (6). Conclusions. These promising findings invite further studies with a larger number of animals and additional brief regimens of irradiation and antibody dosages and specificities.