Prope tolerance: a step in the search for tolerance in the clinic

Following the demonstration by Knechtle and colleagues that profound T cell depletion in rhesus monkeys treated with a CD3 diphtheria immunotoxin resulted in tolerance to renal allografting, we have used a similarly depleting protocol that, in addition, depletes B cells in recipients of a cadaveric renal transplant. The humanized antiCD52 monoclonal antibody had a rapid depleting effect when given intravenously, 20 mg on days 0 and 1 after-renal transplantation, to 31 patients. At 48 hours after the second dose of low dose monotherapy cyclosporine (Neoral) was given to maintain blood levels averaging 100 ng/ml. Initially no other immunosuppression was given. With an average follow-up of 24 months all but one of the patients are alive, 29 with intact functioning grafts. There have been five rejection episodes, which responded to pulsed steroid treatment. One patient had a recurrence of her original disease. Two patients developed opportunistic infections, which responded to therapy; and one patient with severe heart failure at the time of surgery died from this condition after 11 months. Currently 29 patients are still on the original low dose cyclosporine monotherapy. The outcome in this cohort of patients has been encouraging, with efficacy that compares favorably to our conventional triple therapy but in most cases allows the patients to be steroid-free on low dose immunosuppressive monotherapy. The maintenance treatment is inexpensive and should be beneficial in the context of tight budgetary constraints worldwide. The patients who avoided steroids are pleased with this aspect of the protocol. A randomized trial comparing this treatment with standard therapy is planned.