MIXED ALLOGENEIC CHIMERISM AND RENAL-ALLOGRAFT TOLERANCE IN CYNOMOLGUS MONKEYS

We have developed a nonmyeloablative preparative regimen that can prod uce mixed chimerism and renal allograft tolerance between MHC-disparat e nonhuman primates. The basic regimen includes ATG, nonmyeloablative total-body irradiation (TBI, 300 rads), thymic irradiation (TI, 700 ra ds), and donor bone marrow infusion, Kidney allografts from MHC-mismat ched do nors were transplanted with various manipulations of the prepa rative regimen. Monkeys treated with the basic regimen alone (n=2) rej ected allografts by day 15. With the addition of cyclosporine (CsA) fo r one month (n=3), one monkey developed multilineage mixed chimerism a nd renal allograft tolerance thereafter (>430 days). To reduce the tox icity 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 sid e effects and accepted renal allografts long-term with no further immu nosuppression (196 days, 198 days, >150 days, and >40 days), In long-t erm survivors, donor-specific nonreactivity was confirmed by MLR and s kin 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 devel op multilineage chimerism and grafts were rejected (day 40-50) soon af ter the CsA discontinuation. Monkeys treated with the same regimen, bu t without DBM (n=2), rejected kidney allografts by day 52, Therefore, at least transient engraftment of DBM appears to be essential for indu ction of donor specific tolerance in this monkey model.