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Using registered beagle dogs, experiments were performed (1) to develop a technique for the transplantation of a hind limb, (2) to evaluate continuous immunosuppression using antilymphocyte serum, azathioprine, and hydrocortisone to prevent rejection of the transplanted limb, and (3) to explore the effectiveness of an immunological tolerance regimen in which tire host received a brief but intensive treatment with immunosuppressive agents and then was given donor leukocytes as antigen (cross-transfusion or donor spleen cells) with or without prior thymectomy or postoperative splenectomy. The survival times of skin allografts with and without immunosuppressive therapy were also explored.The mean survival times of the skin allografts were ten days with no treatment, eighteen days with azathioprine, 43.2 days with antilymphocyte serum alone, and 73.6 days with rabbit antilymphocyte serum given to dogs with induced tolerance to rabbit immune gamma globulin.Roughly 50 per cent of the transplantations were technical failures, the result of venous or arterial thromboses. Two reimplantations (autografts) were successful, one dog having a virtually normal limb, the other having mild disability at the time of writing, presunmably the result of incomplete regeneration of the peroneal nerve. Six dogs had technically successful limb transplantation (allografts) combined with continuous immunosuppression. Their limbs remained intact for twnty-four, thirty, fifty-three, sixty, seventy-one, and 112 days, respectively. Of these six dogs, three died with their limbs intact (two from generalized sepsis and one from bonemarrow suppression), two were killed because of uncontrollable wound sepsis, and one was killed after it had mauled its unprotected insensitive limb. In these animals it was difficult to titrate the immunosuppression so that rejection was prevented while sepsis and the toxic effects of the immunosuppressive agents were avoided.In three dogs an attempt was made to induce specific immunological tolerance to donor transplantation antigens. Of these dogs, one had rejectins of the transplanted limb at 200 days, another was in good health with motor and sensory function in the limb at 300 days, and the third, followed only sixty days had a wound infection that seemed to have responded to antibiotic therapy at the time of writing. Therefore, tolerance induction had been accomplished in at least two animals.In all instances the first sign of limb rejection was the appearance of small ulcerations of the skin which progressed if appropriate increase in immunosuppression were not made. If rejection was prevented, wound healing, union of the osteosynthesis, and nerve regeneration appeared to progress in essentially the same fashion as after reimplantation.The possible implications of these preliminary experiments in terms of future developments in limb transplantation are discussed briefly.