A comparison of OKT3 monoclonal antibody and corticosteroids in the treatment of acute renal allograft rejection

The monoclonal antibody OKT3 (Ortho Pharmaceutical, Raritan, NJ) was utilized in two separate protocols for treatment of acute renal allograft rejection in patients receiving cyclosporine, azathioprine, and prednisone for maintenance immunosuppression. In Group I, 54 patients received steroids for primary treatment of acute rejection with OKT3 used for resistant rejections and second rejection episodes. In Group II, 34 patients received OKT3 as primary treatment of acute rejection while steroids were used for rescue and second rejection episodes. OKT3 successfully reversed 82% of initial acute rejection episodes in Group II as compared with a 63% reversal with steroids in Group I. Rescue treatment was required in only 15% of Group II patients compared with 33% of Group I patients. Overall patient survival was 96% and 94%, respectively, for steroid primary and OKT3 primary treatments. Allograft survival at 3 months was identical, 74% in both groups. Based on allograft survival data, OKT3 is equally effective either as primary treatment for allograft rejection, or for rescue therapy if initial corticosteroid treatment fails.     

Sequential antilymphocyte globulin/cyclosporine immunosuppression in cadaveric renal transplantation. Effect of duration of ALG therapy

Recent studies have documented the efficacy of quadruple immunotherapy with sequential ALG/cyclosporine in cadaveric renal transplantation. However, the exact role of ALG in this regimen is controversial. Over a four-year period, we performed 429 cadaveric renal transplants (367 primary, 62 retransplants) with prednisone, azathioprine, and the sequential use of Minnesota antilymphoblast globulin (MALG) and CsA. ALG therapy was divided into three protocols: true sequential (n = 259, mean no. days of ALG = 8.2); extended (defined as sequential MALG/CsA continued for 14 days irrespective of renal function or CsA level, n = 103, mean no. days of ALG = 14.1); and therapeutic (continued MALG therapy for early breakthrough rejection, n = 67 [15.6%], mean no. days of ALG = 17.2). The study groups were comparable and retrospectively analyzed in multivariate fashion for 15 variables. Requirement for postoperative dialysis was equivalent (14%) in both sequential and extended ALG groups. Extended ALG therapy failed to reduce the incidence of acute rejection (46.5% vs. 40.4% with true sequential therapy). Prolonging the duration of ALG treatment (greater than 10 days) was associated with a higher risk of infection. Logistic regression analysis revealed that the use of OKT3 after ALG accounted for the higher infection rate. Duration of ALG therapy had no impact on patient or graft survival after a mean follow-up interval of 20 months. We recommended a quadruple immunosuppressive strategy in cadaveric renal transplantation with sequential MALG/CsA to minimize early allograft dysfunction and to achieve excellent patient and graft survival. MALG therapy should be stopped after renal function is documented and CsA levels are therapeutic. Further ALG therapy offers no immunologic advantage and may place the patient at high risk for infection if OKT3 rescue therapy is required.     

OKT3 treatment of steroid-resistant renal allograft rejection

The monoclonal antibody, Orthoclone OKT3 (OKT3), has been used with great efficacy in a prospective multicenter trial as therapy for first rejection episodes in cadaveric donor (CD) renal allograft recipients treated with azathioprine (AZA) and prednisone (P). However, although almost all rejection episodes were reversed, recurrent rejection occurred in approximately two-thirds of OKT3-treated patients in this earlier trial; infections also occurred in about two-thirds of patients, often related to the additional immunosuppression necessary to reverse the rerejection episodes. In the current series of patients, OKT3 was used to treat rejection in CD renal graft recipients in a protocol differing from the multicenter trial in two respects: baseline immunosuppression was cyclosporine (CsA) and P or CsA, AZA, and P (probably more potent immunosuppressive combinations than the AZA and P in the multicenter trial); and OKT3 treatment was reserved for rejection episodes resistant to 3 bolus infusions of methylprednisolone (MP), 5-10 mg/kg, rather than as primary therapy for first rejection episodes. Using this protocol, 46 of 74 rejection episodes (62%) diagnosed between 3/85 and 3/86 in CD renal allograft recipients were treated successfully with MP. Of the remaining 28 steroid-resistant rejection episodes, 27 (96%) were reversed with a 7-14-day course of OKT3, 5 mg/day. Only 5 recurrent rejection episodes (19%) have been observed in the 2-14-month follow-up period after OKT3 treatment; infections have occurred in 10 patients (36%), and three grafts (11%) have been lost in OKT3 treated patients. These results suggest that recurrent rejection and subsequent infection after OKT3 is used to treat rejection may be reduced in a protocol where CD renal allograft recipients are treated with baseline immunosuppression regimens including CsA and where OKT3 is reserved for steroid-resistant rejection. This approach appears to be both more cost-effective than, and as effective therapeutically as, treating all first rejection episodes with the monoclonal antibody.     

OKT3 salvage therapy in a quadruple immunosuppressive protocol in cadaveric renal transplantation

Since the introduction of OKT3 at our center in January 1986, we have performed 246 cadaveric renal transplants (220 primary, 26 nonprimary). All patients received quadruple immunosuppression consisting of prednisone, azathioprine, and the sequential use of Minnesota antilymphoblast globulin (MALG) and cyclosporine. OKT3 (Orthoclone OKT3) therapy was reserved for corticosteroid- and/or ALG-resistant rejection. Of the 246 patients, 138 developed one or more rejection episodes (56.1%). Ninety-seven (70.3%) were successfully reversed with prednisone and/or ALG, whereas 41 (29.7%) required additional treatment with OKT3. Initial graft salvage occurred in 34 (82.9%) patients treated with OKT3, but rejection recurred in 18 (52.9%) and was successfully reversed in only 6 patients. However, the rate of recurrent rejection was much lower in patients given OKT3 early (14%), shortly after it was apparent that high-dose corticosteroid therapy was proving ineffective, than in patients who received OKT3 after a prolonged or second course of corticosteroids (64%) or ALG (60%). Graft survival after a mean follow-up interval of 11 months in all OKT3-treated patients was 54%. One or more infections occurred in 19 (46%) patients treated with OKT3. Patients developing infections following OKT3 therapy received significantly larger total doses of prednisone during graft rejection (46.3 mg/kg vs. 27.9 mg/kg, P less than .05) than OKT3-treated patients who did not develop infectious complications. Our experience shows that use of OKT3 for treatment of corticosteroid- and/or ALG-resistant rejection is associated with a high rate of recurrent rejection, except when given early, as soon as it is clear that high-dose corticosteroid therapy is not reversing the rejection episode. It further suggests that prolonged administration of high-dose corticosteroids and possibly ALG for the treatment of rejection prior to beginning OKT3 greatly increases the rate of infection following OKT3 therapy.     

Inhibition of anti-OKT3 antibody generation by cyclosporine--results of a prospective randomized trial

To investigate the influence of therapy with cyclosporine on the generation of antibodies to OKT3, 51 renal transplant recipients previously maintained on CsA, azathioprine, and prednisone were allocated randomly either to receive 50% of their maintenance dose of CsA (group 1, n = 27) or to discontinue CsA (group 2, n = 24) during treatment with OKT3 for acute renal allograft rejection. In the month following therapy with OKT3, anti-OKT3 antibodies were detected in 11% of patients in group 1 and in 42% of patients in group 2 (P less than 0.02). No patient in group 1 developed antibody titers greater than 1:100, whereas 4 patients in group 2 developed titer greater than or equal to 1:1000. Rejection was reversed in 96% of patients in group 1 and in only 75% of patients in group 2 (P less than 0.03), suggesting that continued administration of reduced doses of CsA during therapy with OKT3 improves the short-term response to this monoclonal antibody. Results of this study suggest that concurrent administration of CsA during therapy with OKT3 inhibits the generation of anti-OKT3 antibodies and improves the response to this monoclonal antibody.     

The treatment of advanced cardiac allograft rejection

Severe cardiac allograft rejection remains a serious problem despite the advances of cyclosporine-based immunosuppression. This study analyzes our experience with 202 recipients of cardiac allografts who were treated primarily with cyclosporine and prednisone. Failure of such therapy in 86 patients (43%) resulted in 105 episodes of advanced cardiac allograft rejection as diagnosed by endomyocardial biopsy. Of 101 rejection episodes that were initially treated with intravenous pulse therapy, 48 (48%) were successfully resolved, yet 60% of these successes were associated with major infections. Patients in whom steroid therapy failed or was contra-indicated received intravenous antithymocyte globulin (ATG) or intravenous monoclonal antibody (OKT3). ATG and OKT3 successfully reversed severe rejection in 26 (81%) of 32 and in 13 (93%) of 14 episodes, respectively. Infectious complication rates were 54% and 21%, respectively. Because the majority (87%) of these rejection episodes occurred within the first 30 days after treatment, many of them may have resulted from inadequate immunosuppressive induction therapy. Based on our results, we believe that advanced cardiac allograft rejection may be managed best by individualizing immunosuppressive therapy, thus enhancing prevention, and by adding OKT3 to the regimen when rejection occurs.     

A prospective comparison of murine monoclonal CD-3 (OKT3) antibody-based and equine antithymocyte globulin-based rejection prophylaxis in cardiac transplantation. Decreased rejection and less corticosteroid use with OKT3

To test the efficacy of murine monoclonal CD-3 antibody (OKT3) in early prophylaxis for cardiac allograft rejection, we conducted a 6-month trial, prospectively assigning 51 patients to receive either equine antithymocyte globulin-based (n = 25) or OKT3-based (n = 26) early prophylaxis. ATG patients received 8 days of ATG (10 mg/kg), with the first dose given preoperatively. OKT3 patients received 14 days of OKT3 (5 mg) beginning on the second postoperative day. Corticosteroid and azathioprine administration were similar during early prophylaxis. Cyclosporine was begun preoperatively in ATG patients and on the fourth postoperative day in OKT3 patients. In addition, patients in both groups were randomized to receive or not receive eight weekly administrations of vincristine (0.025 mg/kg). While infection rate (0.8 +/- 0.2 infections/patient in both groups [mean +/- SEM]) and mortality (1 patient in each group) did not differ, OKT3-based early prophylaxis delayed the first rejection episode (76 +/- 11 days vs. 36 +/- 8 days, P = 0.005) and decreased the risk of rejection during the 6-month follow-up (P less than 0.001, product-limit analysis). Overall, the OKT3 group manifested 1.5 +/- 0.2 episodes of rejection/patient compared with 2.2 +/- 0.2 episodes/patient in the ATG group (P = 0.036). Despite similar 6-month cumulative cyclosporine and azathioprine dosages, six month average corticosteroid administration was less in the OKT3 group (12.2 +/- 1.5 mg prednisone equivalent/m2/day versus 19.3 +/- 2.1 mg prednisone equivalent/m2/day, P = 0.008), fewer OKT3 patients subsequently required additional cytolytic therapy for rejection (2 [8%] versus 12 [48%], P = 0.001), and more patients in the OKT3 group were successfully weaned off maintenance corticosteroids (22 [88%] versus 11 [46%], P = 0.002). We conclude that, relative to an equine ATG-based protocol, OKT3-based early prophylaxis results in less rejection, permitting less chronic corticosteroid administration.     

Cadaveric renal transplantation in the cyclosporine and OKT3 eras

With advances in clinical immunosuppression, results in organ transplantation continue to improve. During a 52-month period, 507 cadaver renal transplants were performed, including 435 primary and 72 nonprimary transplants. All patients were managed with quadruple immunosuppression (prednisone, azathioprine, sequential MALG and cyclosporine). Our experience is divided into pre-OKT3 (n = 228) and OKT3 (n = 279) eras. All kidneys were harvested locally and preserved with pulsatile machine perfusion. The mean duration of preservation was 30.1 hours, with an organ utilization rate of 98.1%. The preservation-related dialysis rate was 13.6%, and primary nonfunction occurred in 8 kidneys (1.6%). Actuarial patient survival in primary and secondary transplant recipients was 90% at 3 years. Overall primary graft survival was 81.6% and nonprimary graft survival, 61.1%. However, the current OKT3 era is characterized by improved patient survival (98% vs 90%, p = 0.001) and primary graft survival (91% vs 80%, p = 0.002) at 1 year when compared with the previous era. Forty-nine patients have received OKT3 therapy, with 31 grafts (63.3%) successfully rescued. Cadaveric renal transplantation with machine preservation, quadruple therapy, and OKT3 rescue is associated with excellent early graft function, reduced acute rejection, and improved patient and allograft survival, even in high-risk recipients.     

Improved solitary pancreas transplant graft survival in the modern immunosuppressive era

The results of solitary pancreas (SP) transplantation have traditionally lagged behind those of simultaneous pancreas-kidney (SPK) transplantation. This is one of the chief factors that has limited the wide-scale application of SP transplantation in nonuremic type I diabetic patients. The purpose of this study is to report our present experience with SP transplantation and compare it to a prior experience. Twenty-three SP transplants (14 PAK, 4 PTA, and 5 PASPK) performed since January 1997 were compared to 56 SP transplants (53 PAK, 1 PTA, and 2 PASPK) performed before 1994. Between 1993 and 1997, SP transplants were not performed because of high morbidity in the early experience. Early SP transplants were performed using bladder drainage of exocrine secretions, and enteric drainage without a Roux-en-Y was used in the recent series. In the early era, immunosuppressive therapy included cyclosporine (CsA), azathioprine (AZA), corticosteroids, and in half of the patients, ALG or OKT3. Recent SP transplants received tacrolimus (TAC). mycophenolate mofetil (MMF), corticosteroids, and induction with either anti-thymocyte globulin (n = 9), OKT3 (n = 1), daclizumab (n = 5), or basiliximab (n = 8). The 1-year Kaplan-Meier patient survival was 85% in the early era and 100% in the recent group of patients (p = 0.08). In the previous era, four patients suffered significant decrement in renal function, necessitating dialysis or kidney transplantation following pancreas transplantation. All patients transplanted since 1997 maintain near prepancreas transplant levels of renal function (mean pretransplant serum creatinine (Cr) 1.3 +/- 0.3 mg/dl vs, mean current Cr 1.4 +/- 0.4 mg/dl, p = NS]. The 1-year Kaplan-Meier graft survival (insulin independence) of recent SP transplants was 87%, whereas for prior SP transplants it was 19% (p = 0.0001). The rate of acute pancreas rejection was significantly different between the two groups. Of early SP transplants, 76% experienced at least one rejection episode within the first year. In contrast, 35% of recent SP transplants suffered acute rejection during the same time period (p = 0.04). Current experience with SP transplantation demonstrates improved graft survival and reduced rejection rates with the use of newer immunosuppressive agents.     

Influence of low-dose cyclosporine on the outcome of treatment with OKT3 for acute renal allograft rejection

The outcomes of 51 consecutive patients who received OKT3 for acute renal allograft rejection were analyzed. Thirty patients (group 1), previously maintained on cyclosporine, continued to receive 50% of their maintenance dose of CsA during OKT3; 21 patients (group 2) either never received CsA or temporarily discontinued CsA during OKT3. All patients received low doses of azathioprine and prednisone during OKT3. Rejection was reversed by OKT3 in 90% of patients in group 1 and in 62% of patients in group 2. Continuation of CsA during OKT3 did not increase the incidence of serious infections following OKT3. Serum creatinine concentrations in groups 1 and 2 were comparable before, during, and after therapy with OKT3 suggesting that low doses of CsA do not induce graft dysfunction during therapy with the monoclonal antibody. In a subset of 22 prospectively studied patients, anti-OKT3 antibodies developed in 2 of 13 patients (15%) who continued low-dose CsA during OKT3 and in 6 of 9 patients (67%) in whom CsA was temporarily discontinued during OKT3. We conclude that administration of low doses of CsA during therapy with OKT3 may reduce the formation of anti-OKT3 antibodies without compromising reversal of rejection by the monoclonal antibody and without increasing the short-term risk of infection or graft dysfunction.     

Use of a brief steroid trial before initiating OKT3 therapy for renal allograft rejection

OKT3 (Ortho Pharmaceutical, Raritan, NJ) has been employed in a protocol where all patients received cyclosporine as part of their baseline immunosuppressive regimen and, after the diagnosis of rejection was established, were treated with up to three pulses of methylprednisolone before monoclonal antibody therapy was initiated. Use of this protocol has allowed 46% of rejection episodes encountered to be treated on an outpatient basis without resorting to inpatient use of OKT3, but has avoided delaying OKT3 therapy until after all other methods of rejection treatment were found to be ineffective. Of 83 rejection episodes treated with OKT3 between March 1985 and May 1987, 78 (94%) were reversed. Overall graft survival is 84% and patient survival is 96% in OKT3-treated patients. Of the 17 rejection episodes where OKT3 treatment was a second or third exposure to the drug, rejection was successfully reversed in 15 (88%). In cadaver donor allograft recipients transplanted between March 1985 and May 1986, actual 1-year graft survival is 80% for 30 patients requiring no rejection therapy, 80% for 20 patients with rejection episodes responding quickly to steroids, and 82% for 28 patients with OKT3-treated, steroid-insensitive rejections. Mean serum creatinine at 1 year posttransplant is 1.5 +/- 0.5; 1.9 +/- 0.7; and 2.1 +/- 0.8, respectively, for these groups of patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Efficacy of tacrolimus in the treatment of refractory rejection in heart and lung transplant recipients.

BACKGROUND: Refractory acute cellular rejection may occur despite triple-drug immunosuppression (cyclosporine A, steroids, azathioprine/mycophenolate mofetil). The purpose of this study was to determine the efficacy of tacrolimus rescue therapy in patients maintained on cyclosporine-based immunosuppression (CBI). METHODS: Between December 1993 and October 1996, 208 patients underwent thoracic organ transplantation at the Hospital of the University of Wisconsin at Madison. One hundred forty-nine patients underwent heart replacement; 59 underwent lung transplantation. One hundred thirty-nine of the heart transplant cohort received CBI preceded by induction therapy with OKT3. Forty-six of the lung transplant cohort received CBI without induction cytolytic therapy. Refractory rejection was defined as failure to respond to high-dose steroids (500 mg to 1 g IV methylprednisolone for 3 days) and/or monoclonal antibody therapy (OKT3, 5 to 10 mg IV/day for 7 to 14 days). In patients with refractory rejection, cyclosporine was replaced with tacrolimus. RESULTS: Overall, 16% (30/185) of patients receiving CBI experienced refractory rejection. Thirty-one episodes of grade IIIa or greater rejection occurred in 11% (15/139) of heart transplant recipients. Twenty episodes of grade II to IV rejection occurred in 33% (15/46) of lung transplant recipients. After tacrolimus rescue therapy, 93% (14/15) of patients in the heart transplant group converted to grade II or less rejection. Refractory rejection was reversed in 73% (11/15) of the lung transplant group. Reversal was documented at biopsy in all (8/8) lung recipients in whom it had been histologically identified. FEV1 values of 3 additional patients stabilized. CONCLUSIONS: The incidence of refractory rejection in thoracic organ transplant recipients on CBI is significant. Reversal of refractory rejection follows rescue immunotherapy with tacrolimus.     

Reexposure to OKT3 in renal allograft recipients

Between 40% and 80% of patients treated with the monoclonal antibody OKT3 develop blocking antibody against its idiotypic region. Thus a major concern with the use of OKT3 as part of a baseline immunosuppressive regimen is that formation of blocking antibodies might preclude its subsequent use. Between 7/86 and 2/87, 32 patients received prophylactic OKT3 in addition to low-dose prednisone, azathioprine, and cyclosporine. Prophylactic OKT3 did not prevent rejection, as 21 of 32 patients studied developed rejection. Retreatment of 13 patients with OKT3 successfully reversed 12 rejections and lowered the number of T3-positive cells in spite of a low level of blocking antibody in two patients in this group. Of the patients analyzed, 38% developed blocking antibody on initial exposure to OKT3, but OKT3 reuse was denied only 4 patients due to the presence of these antibodies. Three of these had rejections reversed with steroids alone; the other patient lost the allograft. A high frequency of infectious complications occurred in the retreatment group, with viral infections predominating. Only one patient in the retreated group developed antibodies after the second use. Appearance of blocking antibodies after use of OKT3 as part of a base-line prophylactic immunosuppressive regimen did not significantly compromise access to OKT3 for treatment of subsequent rejection episodes, but multiple exposures to OKT3 did increase the frequency of infectious complications.     

Prophylactic therapy for rejection after cardiac transplantation. A comparison of rabbit antithymocyte globulin and OKT3

The value of prophylactic monoclonal or polyclonal antibody therapy early after cardiac transplantation is controversial. Between Jan. 1, 1987, and July 1, 1988, 32 consecutive patients underwent cardiac transplantation (cyclosporine, azathioprine, and prednisone maintenance therapy) with either early prophylactic rabbit antithymocyte globulin (n = 17) or monoclonal OKT3 (Ortho Diagnostic Systems, Inc., Raritan, N.J.) (10 days) (n = 15). Follow-up was through Sept. 1, 1988, for morbid events and through Jan. 1, 1989, for survival. All patients (100%) survived the study period (follow-up of 6 to 24 months). The efficacy of rabbit antithymocyte globulin and OKT3 prophylaxis was similar regarding median time (days) to first rejection (16 versus 21 days, p = 0.5), number of rejection episodes during first 2 months (1.5 versus 1.3 days, p = 0.8), and freedom from rejection at 2 months (18% versus 27%, p = 0.8). Early infections were slightly less common in the rabbit antithymocyte globulin group than the OKT3 group (median time to first infection: 318 versus 250 days, p = 0.5; freedom from rejection at 2 months: 82% versus 64%, p = 0.21), although differences were likely due to chance. Cytomegalovirus syndrome was common, with one case of cytomegalovirus pneumonia. T-cell markers during OKT3 treatment did not predict subsequent rejection (within 2 weeks after OKT3) as assessed by mean T3-lymphocyte count during OKT3 use (p = 0.3) or T3-lymphocyte count during the last 3 days of OKT3 use (p = 0.4). Inferences: (1) Prophylactic rabbit antithymocyte globulin or OKT3 with triple-drug immunosuppression yields excellent intermediate survival after heart transplantation. (2) These protocols for rabbit antithymocyte globulin and OKT3 provide similar protection against early rejection with a relatively low risk of early infection. (3) T-cell markers do not predict early rejection after OKT3.     

Antilymphocyte globulins versus OKT3 as prophylactic treatment in highly sensitized renal transplant recipients

Abstract Monoclonal antibodies were proposed as an effective prophylactic immunosuppressive treatment in highly sensitized patients (HSP). In this study we compared the results obtained in HSP treated with OKT3 or antilymphocyte globulins (ALG). From January 1989 to January 1993, 38 transplantations were performed in patients with high panel reactive antibodies (PRA>50%). The group comprised 22 women and 16 men, mean age 45 ± 2 (23–67) years; ten were second grafts and two were third grafts. Peak PR A was ≥ 80% in 24 sensitized patients and 50–80% in 14 sensitized patients. Patients were randomly assigned to either prophylactic OKT3 ( n = 15) or ALG ( n = 23). Oral cyclosporin A (10 mg/kg) was started at day 8 in the OKT3 group and when the serum creatinine level decreased to 200 μymol/l in the ALG group. OKT3 was systematically withdrawn on day 10 but ALG was stopped only when total blood cyclosporin A concentration reached 150–200 ng/ml. In both groups, azathioprine (150 mg/day) and prednisolone were given. During the first months, 6/15 grafts were lost in the OKT3 group (three hyperacute rejections, one renal vein thrombosis, one steroid-resistant rejection, one death); in the ALG group 4/23 grafts were lost (one hyperacute rejection, two steroid-resistant rejections, one death). Side effects were significantly more frequent in the OKT3 group than in the ALG group. After 12 months of follow up, the graft survival was 71% (27/38) and did not significantly differ (log-rank test, NS) between the OKT3 (60%, 9/15) and the ALG group (78%, 18/23). We conclude that the use of the monoclonal antibody OKT3 as a prophylactic agent in HSP does not improve the early graft survival when compared with prophylactic ALG. Polyclonal antibodies, which react with many epitopes and are much better tolerated seem to offer a good strategy for induction therapy in this population.     

Neoquadruple induction with antithymocyte globulin/azathioprine/cyclosporine/prednisolone in simultaneous pancreas and kidney transplant recipients: 8.5-year results

Ten years ago therapy with antithymocyte globulin or OKT3, azathioprine, cyclosporine, and prednisolone was the most common induction treatment for simultaneous pancreas/ kidney (SPK) recipients. Although immunosuppression was started after surgery, there was a high incidence of acute rejection episodes. In 1995, we modified the application of antithymocyte globulin and prednisolone by starting prior to reperfusion. Between 1995 and 1996, 30 patients underwent a first SPK. Prior to reperfusion, antithymocyte globulin (4-6 mg/kg body weight) and 250 mg prednisolone were administered. Intraoperatively, another 250 mg prednisolone were administered as well as intravenous azathroprine 3 mg/kg. After surgery up to 10 doses of antithymocyte globulin were administered and cyclosporine trough levels targeted to 200 to 250 ng/mL. Prednisolone was reduced gradually. After a median period of 8.5 years (range: 7.8-9.5 years) patient, pancreas, and kidney graft survival were 93.3%, 70%, and 76.7%, respectively. Sixteen acute rejection episodes were diagnosed in 11 patients (36.7%), who were treated with prednisolone bolus (n = 4), prednisolone with OKT3 (n = 8), prednisolone with antithymocyte globulin (n = 1), cyclosporine to tacrolimus conversion (n = 2), or plasmapheresis (n = 1). Two recipients died after SPK due to severe infection or carcinoma with functioning grafts. Seven further pancreas grafts were lost. Five kidney losses were observed besides the two recipients who died with functioning grafts. While previous protocols yielded a rejection incidence after SPK between 50% and 80%, we observed 60% of patients with no rejection episode during an 8.5-year median follow-up.     

Antilymphocyte globulin versus OKT3 induction therapy in cadaveric kidney transplantation: a prospective randomized study.

Different induction therapies have been used in renal transplantation to avoid cyclosporine (CsA) nephrotoxicity and early acute graft rejection. This study compares the efficacy of a short course of prophylactic OKT3 to that of antilymphocyte globulin (ALG) in preventing acute renal allograft rejection when administered concomitantly with CsA and steroids. Between March 1988 and December 1990, 140 first-cadaver renal transplant recipients were randomly allocated to two immunosuppression groups--ALG group (n = 68): ALG 15 mg/kg just before transplant surgery, ALG 12 mg/kg the first day after transplant, followed by four doses of 10 mg/kg on alternate days; and OKT3 group (n = 72): OKT3 5 mg just before transplant, followed by four doses of 5 mg/d. Both groups included low-dose CsA and steroids. The incidence of rejection during the first 3 months after transplantation was 15% in the ALG group and 19% in the OKT3 group (NS). Kaplan-Meier estimates of patients free of rejection at 2 years was 85% in the ALG group and 77% in the OKT3 group (NS). The 3-year actuarial graft survival was 82% and 85% (NS), and 3-year patient survival was 97% and 98% (NS), in the ALG and OKT3 groups, respectively. These results indicate that the concomitant association of CsA and ALG or OKT3 constitutes a safe and effective therapeutic strategy that provides a low incidence of rejection and gives good results for patient and graft survival.     

A prospective study on the use of monoclonal anti-T3-cell antibody (OKT3) to treat steroid-resistant liver transplant rejection

Conventional treatment of acute liver allograft rejection has included high doses of corticosteroids and antithymocyte globulin. Urgent retransplantation was the only option for patients who failed to respond. We report our initial experience with the use of monoclonal anti-T3-cell antibody (OKT3) in 25 patients with acute hepatic allograft rejection that was resistant to steroid and/or antithymocyte globulin therapy. Twenty-four of 25 patients had a response to OKT3, which was complete in 14 and partial in ten. With a mean follow-up of 8.2 months, allograft salvage has been 80% and patient survival 88%; two patients underwent successful retransplantation. Side effects have been mild and well tolerated. Repeated rejection has occurred in 40% of patients, but these episodes have responded to steroid therapy. We conclude that OKT3 is well tolerated and highly effective in reversing severe episodes of acute hepatic allograft rejection that is resistant to high-dose steroid therapy.     

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.     

Randomized prospective trial of OKT3 for early prophylaxis of rejection after liver transplantation

A group of 52 liver transplant patients was prospectively randomized to receive prophylactic immunosuppressive therapy consisting of either Orthoclone OKT3 for 14 days, azathioprine, and steroids (25 patients); or cyclosporine, azathioprine, and steroids (27 patients). The groups were similarly matched for age, diagnosis, and Child's classification. The patients were studied to determine the effect of these two regimens on the incidence of rejection, infection, renal dysfunction, and mortality. Seven rejection episodes, as determined by clinical and histological criteria, occurred in seven of 25 patients (28%) receiving OKT3 compared with 18 episodes in 27 patients (67%) receiving cyclosporine during the first 14 days after transplantation (P less than 0.02). In 20% of the OKT3 patients, CD3+ levels of greater than 10% developed during therapy, and 16% of the patients developed anti-OKT3 antibodies during OKT3 treatment. Five patients were retreated with OKT3 for steroid-resistant acute rejection episodes; all had resolution of the rejection episode. Infectious complications were similar in each group. Renal function, as measured by serum creatinine, was significantly better with OKT3 than with cyclosporine (P less than 0.003) at 14 days. We conclude that prophylactic OKT3 is effective in reducing the number of early rejection episodes after liver transplantation; after 14 days the incidence of rejection is similar; reuse of OKT3 has been successful in liver transplant patients; infectious complications are similar between OKT3 and cyclosporine; and OKT3 preserves renal function better than cyclosporine and is thus indicated in patients with compromised preoperative renal function.