Monoclonal antibody OKT3 therapy in pediatric kidney transplant recipients.

Thirty-one pediatric patients with acute renal allograft rejection were treated with the monoclonal antibody OKT3. In 24 cases, increased doses of steroids followed by a polyclonal antithymocyte globulin were ineffective in reversing the rejection episode. Twenty-eight patients completed the prescribed minimum 10-day treatment course, with effective rejection reversal in 22. Three patients failed to complete the course of therapy: one because of leukopenia that developed after the first dose, one because of a clotted graft, and another because of symptomatic cytomegalovirus infection. The overall success rate of OKT3 for rejection reversal was 74%; however, 55% of recipients had rebound rejection, and 85% of patients had detectable anti-OKT3 antibodies after completion of the course of therapy. Ten patients were treated with a second course of OKT3, and in eight of these patients, rejection was at least temporarily reversed. The starting dose of OKT3 for second-course therapy was the same as that used during first-course therapy, but in five cases the dose was increased during the course because of inadequate therapeutic response. Seven of these patients lost their grafts a mean of 6.5 months after completion of second-course therapy. We looked for anti-OKT3 antibody in nine recipients after completion of a second treatment course and found it in all nine. Our observations regarding a second treatment course with this monoclonal antibody preparation suggest that although rejection reversal may be observed, ultimate graft survival is poor and anti-OKT3 antibody formation is enhanced.

Effectiveness of a second course of OKT3 monoclonal anti-T cell antibody for treatment of renal allograft rejection.

A second course of OKT3 monoclonal anti-T cell antibody was given to 21 recipients of kidney transplants. Rejections reversed in 43% of patients in whom 95% of rejections had reversed with their initial OKT3 course. Reversal was highly dependent upon the timing of rejection, anti-OKT3 antibody production, and T cell CD3 modulation. Rejections treated greater than 90 days after transplantation were resistant to OKT3 reversal. High-titer anti-OKT3 antibodies prevented OKT3 reversal of rejection, and effective CD3 (the cell surface target of OKT3) modulation was necessary for successful OKT3 reversal of rejection. Reexposure to OKT3 further stimulated anti-OKT3 antibody production and broadened the specificity of the antibodies produced. OKT3 can effectively and safely be used a second time for treatment of early T cell-mediated renal allograft rejections if high-titer anti-OKT3 antibodies have not been made.

Early use of OKT3 monoclonal antibody in renal transplantation to prevent rejection.

OKT3 monoclonal anti-T cell antibody was used during the first 2 weeks following cadaveric renal transplantation to prevent rejection. When compared with a control group receiving triple immunosuppression with cyclosporine, azathioprine, and prednisone, the OKT3, azathioprine, and prednisone group had significantly fewer acute rejections during the first month (6% v 50%; P less than 0.01), and the mean time of onset of the first rejection was significantly delayed (day 47 v day 8; P less than 0.01) in the OKT3 prophylaxis group. OKT3 was administered intraoperatively safely and without complications on the day of transplantation. The well-reported first dose reaction to OKT3 was similar in these patients when compared with patients receiving OKT3 for treatment of rejection. Anti-OKT3 antibody development occurred in half of the patients receiving OKT3, and did not prevent the subsequent use of OKT3 in these patients, whose rejections following OKT3 prophylaxis were steroid reversible. There were no deaths among the patients receiving prophylactic OKT3, and during a 15-month follow-up, only three of 34 kidneys were lost for any reason. In addition to its use for primary and steroid-resistant rejection, OKT3 may be useful early after transplantation to prevent rejection.

The use of OKT3 in cadaveric renal transplantation for rejection that is unresponsive to conventional anti-rejection therapy.

Thirty-one recipients of cadaver kidney transplants were given OKT3 monoclonal anti-T cell antibody for rejection treatment after conventional therapy had failed. Seventy-four percent of steroid or steroid and antithymocyte globulin (ATG) resistant rejections reversed with a standard course of OKT3. Rejections reversed in 85% of 26 patients treated within 90 days of transplantation. Late rejections treated more than 90 days after transplantation were poorly responsive to OKT3 and graft survival for this group of five patients was poor (20%). However, for those patients treated with OKT3 for early resistant rejection, actuarial 4-year graft survival was 66%. Actuarial 4-year patient survival was 97%, and the incidence of serious infection was low. Acute rejections in cadaver transplantation are common and a small percentage of rejections are resistant to steroids and ATG. OKT3 has proven to be useful for reversing these resistant rejections without causing significant morbidity from infection or death.

OKT3 monoclonal antibody in pediatric kidney transplant recipients with recurrent and resistant allograft rejection.

Twelve pediatric patients, aged 28 months to 17 years, received OKT3 to reverse renal allograft rejection. In 11 patients, the rejection crisis was resistant to conventional antirejection therapy with high doses of prednisone or polyclonal antithymocyte globulin. Reversal of rejection was successful in 10 patients who completed a treatment course. Because of recurring resistant rejection, five patients received a second course of OKT3, which was successful in reversing the rejection crisis in two. Among these patients, the persistence or the appearance of high levels of circulating T3 lymphocytes after initiating the second treatment course correlated with treatment failure. The immediate side effects associated with OKT3 therapy were transient and medically manageable. We conclude that this monoclonal antibody preparation is a safe and effective treatment for pediatric renal allograft in recipients experiencing rejection crisis resistant to conventional therapy. However, the potential impact of this immunosuppressive medication on long-term renal allograft survival in this patient population remains to be determined.

Therapeutic use of OKT3 monoclonal antibody for acute renal allograft rejection.

OKT3, a murine monoclonal anti-T-cell antibody, was used to treat acute renal allograft rejection crises in 140 patients. When used for primary treatment of initial rejections, it was effective in all 20 recipients of related-donor (RD) grafts and in 70 of 74 recipients of cadaver-donor (CD) grafts. OKT3 was also used for resistant rejection unresponsive to conventional antirejection drugs and was effective in 11 of 13 RD and in 26 of 33 CD recipients. Rerejection occurred in 58% of patients in the OKT3 primary treatment group and in 35% of patients in the OKT3 rescue group. Fifty-nine percent of the patients produced anti-OKT3 antibodies. Nearly all recipients experienced a flu-like syndrome following the first and second daily doses of OKT3. Two-year actuarial patient survivals were 100 and 96% for RD and CD recipients, respectively. In the OKT3 primary treatment group, two-year actuarial RD and CD graft survivals were 91 and 76%, respectively. In the OKT3 rescue group, the two-year actuarial RD and CD graft survivals were 85 and 55%, respectively. A proposed immunosuppressive effect of OKT3 is T-cell inactivation by blocking antigen receptors linked to OKT3-reactive molecules. Reuse of OKT3 for recurrent rejection or subsequent organs may be hampered by anti-OKT3 antibody production. OKT3 is an effective steroid-sparing treatment for renal allograft rejection.