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.
Kawai
T
T
General Surgical Service, Massachusetts General Hospital, Boston.
Cosimi
A B
AB
Colvin
R B
RB
Powelson
J
J
Eason
J
J
Kozlowski
T
T
Sykes
M
M
Monroy
R
R
Tanaka
M
M
Sachs
D H
DH
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