MIXED ALLOGENEIC CHIMERISM AND RENAL-ALLOGRAFT TOLERANCE IN CYNOMOLGUS MONKEYS

We have developed a nonmyeloablative preparative regimen that can produce mixed chimerism and renal allograft tolerance between MHC-disparate nonhuman primates. The basic regimen includes ATG, nonmyeloablative total-body irradiation (TBI, 300 rads), thymic irradiation (TI, 700 rads), and donor bone marrow infusion, Kidney allografts from MHC-mismatched do nors were transplanted with various manipulations of the preparative regimen. Monkeys treated with the basic regimen alone (n=2) rejected allografts by day 15. With the addition of cyclosporine (CsA) for one month (n=3), one monkey developed multilineage mixed chimerism and renal allograft tolerance thereafter (>430 days). To reduce the toxicity of the preparative regimen, TBI was fractionated to 150 rads on two successive days in subsequent studies. All monkeys receiving this modified regimen (n=4) developed multilineage chimerism with fewer side effects and accepted renal allografts long-term with no further immunosuppression (196 days, 198 days, >150 days, and >40 days), In long-term survivors, donor-specific nonreactivity was confirmed by MLR and skin transplantation. Three monkeys treated with the basic regimen plus CsA but with only 150 rads of TBI (n=1) or no TBI (n=2) did not develop multilineage chimerism and grafts were rejected (day 40-50) soon after the CsA discontinuation. Monkeys treated with the same regimen, but without DBM (n=2), rejected kidney allografts by day 52, Therefore, at least transient engraftment of DBM appears to be essential for induction of donor specific tolerance in this monkey model.