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 donors 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.
General Surgical Service, Massachusetts General Hospital, Boston.
T
T
Kawai
A B
AB
Cosimi
R B
RB
Colvin
J
J
Powelson
J
J
Eason
T
T
Kozlowski
M
M
Sykes
R
R
Monroy
M
M
Tanaka
D H
DH
Sachs
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000961:Antilymphocyte Serum / Q000494:pharmacology; D016026:Bone Marrow Transplantation / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D006085:Graft Survival / Q000276:immunology*; D007108:Immune Tolerance; D007165:Immunosuppression Therapy / Q000379:methods; D016030:Kidney Transplantation / Q000276:immunology* / Q000379:methods; D008252:Macaca fascicularis / Q000276:immunology*; D008297:Male; D018183:Transplantation Chimera / Q000276:immunology*; D014916:Whole-Body Irradiation
D000911:Antibodies, Monoclonal; D000961:Antilymphocyte Serum; D017252:CD3 Complex