Long-term Incompatible Kidney Survival in Outbred Higher Primates without Chronic Immunosuppression

Abstract

Transplantation between non-identical humans has been limited by the requirement for chronic immunosuppression (CI). This study demonstrates in a nonhuman primate model that long-term acceptance of incompatible kidney allografts can be achieved without the use of CI. Following incompatible kidney transplantation, rhesus monkey recipients were given a 5-day course of clinical rabbit antithymocyte globulin (RATG). On day 12, unfractionated donor bone marrow (BM) was infused intravenously. Recipients were monitored for T-cell levels and T-cell subset levels with monoclonal antibodies and for responses in one way MLR. Graft survival in untreated control animals was 9.2 +/- 2.8 days. In six animals given RATG only, all died of rejection at a mean 35.8 +/- 5.7 days. Of five animals given RATG and donor BM (mean 2.5 RhLA mismatches, mean MLC 12.7), four are alive at 150 days, 248 days, 342 days, and 401 days (median 248 days). The ATG-BM infused group showed a prolonged imbalance of their OKT4/OKT8 cell ratio and cellular suppression of MLR responsiveness. The long-term survival obtained in these outbred primates is apparently due to a synergistic immunoregulatory effect induced by the RATG and donor BM. The model described is apparently the first report of long-term survival of outbred higher primates without CI and may represent a technique for producing tolerance without CI in the human.

Lymphodepletional Strategies in Transplantation

“…Thomas et al observed that kidney transplanted rhesus macaques receiving 50 mg/kg of rATG for 5 days followed by a single infusion of unfractionated donor bone marrow on day 12 experienced longterm survival past 248 days without evidence of graft versus host disease, infection, or rejection (compared to 35.8 days for rATG alone, p , 0.001); a second donor bone marrow infusion on day 24 reversed the benefit, however, as the animals rejected with a mean graft survival time of 76.6 days (Thomas et al 1983). In revisiting the ATG þ dBM model, the group observed a reduced median survival of 70 days, still a considerable feat in the absence of chronic immunosuppression (Thomas et al 1989).…”

Bone Marrow Augmentation in Renal Transplant Recipients

“…Approximately a decade later, encouraged by Judy Thomas's work with the primate model, 14,15 Monaco performed three living-related kidney/bone marrow transplantations, using the same triple drug induction therapy (including ALG) and administration of 3 to 5 × 10 8 cryopreserved bone marrow cells/kg on postoperative day 21. 16 Two of the recipients did well, with no evidence of rejection at 11 and 13 months after transplantation, and had evidence of decreasing donor-specific responsiveness.…”

Donor MHC Class II Antigen Is Essential for Induction of Transplantation Tolerance by Bone Marrow Cells

“…Tolerant mice showed evidence of low degree (up to 4%) chimerism (microchimerism) (3). Subsequent studies in mongrel dogs (4,5) and nonhuman primates (6,7) demonstrated that the use of polyclonal ALS and donor BMC is also very effective in producing tolerance to kidney allografts. Posttransplant donor BMC infusion with induction therapy by polyclonal antilymphocyte globulin was clinically applied in living-related and cadaveric kidney transplantation with a standard multidrug immunosuppressive protocol (8 -10).…”