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.     

Experience with OKT3 in vascularized pancreas transplantation

With refinements in technical aspects of whole organ pancreas transplantation, allograft rejection is currently the major cause of graft failure. The monoclonal antibody OKT3 has emerged as a highly effective antirejection therapy in renal and hepatic allograft recipients, but its efficacy in pancreas transplantation remains to be determined. During a 12-month period, 28 vascularized whole organ pancreas transplants were performed with pancreatico-cystostomy. Sixteen episodes of allograft rejection were treated with monoclonal antibody OKT3. Indications for OKT3 use included steroid- or antilymphocyte globulin (ALG)-resistant allograft rejection in isolated pancreas (n = 8) or simultaneous kidney-pancreas (n = 8) transplants. A total of 34 rejection episodes occurred in the 16 patients (mean, 2.1; range, one to five). The diagnosis of rejection was based on clinical criteria, a reduction in urinary amylase clearance, radionuclide scanning, hyperglycemia, or associated renal allograft dysfunction in combined engraftments. Postoperative immunosuppression consisted of cyclosporine, prednisone, azathioprine, and prophylactic ALG. OKT3 was administered for a full 14-day course concomitant with low-dose steroids, azathioprine, and cyclosporine. The mean age of the patient population was 32.1 years (range 24 to 39) with a mean duration of insulin-dependent diabetes mellitus (IDDM) of 20.9 years. Monoclonal antibody therapy was instituted in two clinical settings: early rejection (within 3 months of transplant, n = 10); and late rejection (after 3 months, n = 6). OKT3 successfully reversed allograft rejection in ten (62.5%) cases, including six early (60%) and four late (66.7%) episodes. In isolated pancreas transplants, OKT3 therapy reversed pancreas allograft rejection in only two patients (25%).(ABSTRACT TRUNCATED AT 250 WORDS)     

OKT3 serum levels as a guide for prophylactic therapy: a pilot study in kidney transplant recipients

The use of OKT3 as prophylaxis in renal transplantation results in a reduced incidence of graft rejection and appears to have beneficial effects on long-term kidney graft survival. However, we and others have observed that patients still experience rejection during the period of OKT3 prophylaxis given at the regular 5 mg/day dose. Many of these patients had no circulating CD3⁺ cells at the time of rejection, but their OKT3 serum levels were distinctly low (<500 ng/ml). This led us to adjust OKT3 doses (5 or 10 mg) daily, according to the patients' OKT3 levels, in order to maintain an OKT3 concentration of around 1000 ng/ml. In addition, patients were randomized to receive either 5 mg (group 1, n=15) or 10 mg (group 2, n=14) OKT3 as the initial three doses. Concomitant immunosuppression consisted of azathioprine and steroids, with the introduction of cyclosporin A on day 11. Patient survival was 100% after 3 months of follow-up. The intensity of OKT3 first-dose reactions was similar in both groups. Intragraft thrombosis, initially observed in a previous group of patients who received a fixed 10 mg/day OKT3 prophylaxis, occurred in three patients in group 1 and resulted in two graft losses. The cumulative OKT3 dose was similar in both groups (mean ± SEM 98±2 mg in group 1 vs 102±3 mg in group 2) and higher than the 70 mg usually administered. Group 2 patients had higher OKT3 serum levels during the first 4 days of therapy. No correlation could be found between patient weight and cumulative OKT3 dose (r=0.29). No patient in either group 1 or 2 experienced rejection during OKT3 therapy. This compared favorably with an historical group of kidney recipients treated with a fixed 5 mg/day OKT3 dose, as 6 out of 32 patients in this group developed rejection (P=0.045). The rejection rate up to 3 months post-transplantation in pooled group 1 and 2 patients was low (six episodes per 81 patientmonths of risk exposure). We conclude that adaptation of the OKT3 dose according to daily OKT3 levels is safe and allows for excellent prevention of early graft rejection.     

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.     

OKT3 therapy for hepatic allograft rejection. Differential response in adults and children

The clinical courses following OKT3 therapy for hepatic allograft rejection (HAR) in adults and children have not been individually defined. We have reviewed our experience with OKT3 therapy for HAR in adults and children to compare: (1) the initial response to OKT3 therapy, (2) the clinical course following OKT3 therapy, and (3) the antimurine antibody response and immunologic monitoring results. Children required OKT3 therapy more frequently than adults: fourteen courses of OKT3 therapy were required in 130 orthotopic liver transplants (OLT) in 108 adult patients, whereas nineteen courses of OKT3 therapy were required in 94 OLT in 78 children (P less than 0.02). Repeat OKT3 therapy was not required in adults--however, four of nineteen courses of OKT3 therapy in children were repeat OKT3 therapy for rejection. No differences existed between adult and pediatric treatment groups with respect to number of prior OLT procedures, previous graft loss to rejection, percentage of ABO-incompatible grafts, frequency of positive donor-recipient lymphocyte crossmatches, or time to first rejection. The initial response to OKT3 therapy (rapid reversal, delayed reversal, and failure) was remarkably similar in adults and children. However, nine of 13 (70%) children with clear evidence of response to OKT3 treatment experienced breakthrough rejection or early recurrent rejection, whereas none of 12 adults suffered breakthrough rejection or early recurrent rejection (P less than 0.01). Early recurrent rejection did not correlate with delayed reversal of rejection, early return of CD3+ cells by peripheral blood monitoring, or development of anti-OKT3 antibodies. All 4 courses of OKT3 retreatment in children were successful in reversing rejection, and breakthrough rejection and early recurrent rejection did not occur. Overall graft and patient survival in pediatric patients requiring OKT3 therapy (67% and 73%) was not different from that in adults (71% and 79%). Results obtained in one patient provide the first evidence that successful OKT3 retreatment of HAR can be achieved in the presence of preexisting idiotypic anti-OKT3 antibody. In conclusion, OKT3 therapy for HAR was required more frequently in children than in adults. The clinical outcome following OKT3 therapy for HAR also differs markedly, with early recurrent rejection and breakthrough rejection occurring more frequently in children.     

High or low dose steroid therapy for acute renal transplant rejection after prophylactic OKT3 treatment: a prospective randomized study

In this prospective randomized study, acute renal transplant rejections occurring in patients who received prophylactic OKT3 therapy were treated with either 3 pulses of 8 mg/kg methylprednisolone (MPS) in an alternate-day regimen (total dose 25 mg/kg in 1 week, H group, n = 24) or 5 daily pulses of 3 mg/kg MPS (total dose 17 mg/kg, L group, n = 22). Acute rejection was proven by biopsy in more than 85% of cases in both groups. No difference was observed in rejection reversal (H 88%, L 91%), graft losses in the following 3 months (H 11%, L 4%) or the time evolution of the serum creatinine levels. The number (H 14, L 21) as well as the nature and severity of infections were similar in both groups. Only one death occurred in a patient who received OKT3 rescue therapy for corticoresistant rejections and developed Epstein-Barr virus (EBV)-related lymphoma. In conclusion, low dose MPS pulses appear as effective and safe as a higher dose to reverse acute rejection occurring after OKT3 prophylaxis. Thus, we favour the use of the low dose regimen in these patients.     

Initial results of solitary pancreas transplants performed without regard to donor/recipient HLA mismatching

BACKGROUND: We hypothesized that solitary pancreas transplants could be performed successfully even in the presence of poor HLA matching if an aggressive approach were taken with regard to immunosuppressive protocol and the performance of allograft biopsy. METHODS: Seven pancreas-after-kidney transplants and seven pancreas transplants alone were performed without consideration given to the degree of HLA mismatching (MM) using tacrolimus (FK506)/mycophenolate mofetil (MMF)/prednisone maintenance therapy. Mean (+/-SD) total HLA MM was 4.8+/-1.2. All patients were followed for at least 6 months. The first four cases were induced with ATGAM for 7 to 10 days. In the remaining 10 cases, an ultrasound-guided percutaneous needle biopsy was attempted on a protocol basis 10 days after completing induction with OKT3 for 7 (n=2) or 14 (n=8) days. RESULTS: Overall patient survival, graft survival, and incidence of acute rejection requiring treatment were 86, 79, and 50%, respectively. Two patients receiving ATGAM developed grade III-IV rejection at 3 weeks. Both patients receiving OKT3 for 7 days developed early grade III rejection. However, only three of eight patients receiving OKT3 for 14 days developed rejection requiring treatment. Protocol biopsy was successfully performed in six of seven patients and uncovered three cases of otherwise undetectable grade III-IV rejection. CONCLUSIONS: Although based on a small number of cases, our results suggest that solitary pancreas transplants with a poor HLA match can be performed with an acceptable rejection incidence and graft survival rate using an OKT3/FK506/MMF/prednisone regimen with protocol biopsy.     

The efficacy of OKT3 in vascular rejection

Sixty-six consecutive biopsies of renal allograft recipients treated with OKT3 monoclonal antibody were reviewed and placed into one of two groups. Group I (29 patients) had evidence of acute vascular and cellular rejection, while group II (32 patients) had cellular rejection but no vascular rejection. In 5 cases, the sample was inadequate to determine if vascular rejection was present or not. The severity of the cellular rejection was graded histologically as mild, moderate, or severe. The severity was equivalent when comparing group I with group II (mild, 17% vs. 10%; moderate, 52% vs. 59%; and severe, 31% vs. 31%). There was no difference in the rejection reversal rate between the two groups (86% vs. 91%). However, at 6 and 12 months there was a higher graft loss in the group with vascular rejection (graft survival 64% vs. 81%, P = 0.13, and 58% vs. 75%, P = 0.08, respectively). The poorest outcome was in those patients with both severe acute cellular rejection and acute vascular rejection (4/9, or 44%). The serum creatinine level was higher both pre- and post-OKT3 therapy and at 1, 6, and 12 months in the group with vascular rejection. In conclusion, OKT3 was equally successful in reversing acute cellular rejection and acute vascular rejection. However, increased graft loss occurred at 6 and 12 months in the group with vascular rejection.     

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)     

Evaluation of OKT3 monoclonal antibody and anti-thymocyte globulin in the treatment of steroid-resistant acute allograft rejection in pediatric renal transplants

We reviewed the effectiveness of Muromonab-CD₃ (OKT3) and anti-thymocyte globulin (ATG) in the treatment of corticosteroid-resistant acute renal allograft rejection in 49 transplanted children. Reversal of rejection was successful in 22 of 23 patients (96%) treated with OKT3 and 21 of 26 (81%) treated with ATG (P=NS). Re-rejection episodes occurred within 1 month of cessation of therapy in 9 of 22 patients treated with OKT3 but only in 2 of 21 who received ATG (P<0.05). In the patients with re-rejection, 7 of the 9 patients originally given OKT3 and 1 of the 2 who received ATG responded to a repeat course of high-dose corticosteroids; thus, at 1 month post treatment, the incidence of graft loss due to initial rejection or re-rejection was 13% for the OKT3 and 23% for the ATG group (P=NS). Graft survival was similar at 6 months: 82% for OKT3- and 73% for ATG-treated patients (P=NS); 100% patient survival was noted in both groups. Mean calculated creatinine clearance prior to, during, and at 1 and 6 months post rejection was similar in the OKT3- and ATG-treated groups. Neutropenia and thrombocytopenia occurred more frequently in the ATG group, but there was no significant difference in infectious complications. Two patients developed high (1:1,000) OKT3 antibody titers. In our experience, children with corticosteroid-resistant acute renal allograft rejection treated with OKT3 and ATG had similar allograft survival and level of renal function at 1 and 6 months, and number of infectious complications post therapy.     

Complications and monitoring of OKT3 therapy

Complications of OKT3 therapy were studied in 122 treatment episodes in renal allograft recipients (83 for rejection treatment, 39 for immunosuppression induction). A febrile first-dose reaction to OKT3 was common; no severe pulmonary complications were encountered. Other toxicities of OKT3 therapy were observed later in the treatment course. Most severe were the occurrence of aseptic meningitis in four patients (3%), and seizures in eight (6%). Seizures occurred only when OKT3 was given to patients with nonfunctioning grafts due to acute tubular necrosis. Infections were the only significant late adverse sequelae of OKT3 therapy and occurred more frequently after multiple exposures to the drug (53%) than after a single exposure (22%). IgG antibodies to OKT3 developed after 45% of exposures to the drug in the 74 patients in whom appearance of anti-OKT3 antibodies was monitored. In two patients (3%), anti-OKT3 antibodies were detected before the end of the OKT3 treatment course, neutralizing the immunosuppressive property of the drug. In five patients (7%), strong anti-OKT3 antibody responses were present at the time of subsequent rejection, which precluded reuse of the drug. In 17 other cases, no or only a weak anti-OKT3 response was detectable at the time of rejection following initial OKT3 exposure. Retreatment with OKT3 was successful in reversing rejection in 15 cases (88%). No untoward sequelae were noted after reexposure to OKT3, except the high incidence of subsequent infections.     

Induction versus noninduction therapy in kidney transplantation: considering different PRA levels and different induction therapies

To evaluate the rate of acute cellular rejection (ACR) and long-term results in different levels of anti-HLA sensitization, using noninduction or different induction therapies, 763 patients who underwent transplantation from January 1995 to December 2001 were evaluated: 213 patients received induction therapy, 71 received Thymoglobulin (Thymo), 66 Simulect, and 44 OKT3. Follow-up time was at least 1 year for all groups. The Simulect group included older recipients and the OKT3 group had more female patients. Simulect and OKT3 groups had more black patients; Thymo and OKT3 groups had more retransplantations. PRA was low in the noninduction group (mean, 7%) and about the same in the Simulect and Thymo groups (mean, 30%). OKT3 was the most sensitized group (mean = 59%). Dialysis during the first posttransplantation week was more frequent among the induction groups (43% vs 65%; P <.005). Fewer patients experienced rejection episodes in the Thymo group (20% vs 50%; P =.02). Patients were classified according to their level of sensitization, and the Thymo group showed the lower rejection rates in all levels (mean, 20%; P =.001). When analyzing PRA >50%, the Thymo group showed lower rejection rates (12% vs 50%; P =.02). At this level of sensitization, there was no significant difference on graft loss and death with a functioning graft. There was a trend to more cytomegalovirus (CMV) disease in the Thymo group (33% vs 23%; P =.08). Two PTLD were diagnosed, both in the noninduction group. Renal function was better in the Thymo group (1.3 mg/dL). In conclusion, Thymo showed lower ACR rates in all PRA groups. No significant differences in CMV infection, tumors, and patient survival were observed.     

Treatment of acute cellular rejection with T10B9.1A-31 or OKT3 in renal allograft recipients.

T10B9.1A-31, a nonmitogenic immunoglobulin Mk monoclonal antibody that detects an epitope on the alpha/beta chains of the T cell antigen receptor (TCR alpha/beta), or OKT3, an anti-CD3 mAb, was employed in a randomized double-blind phase II clinical trial to treat biopsy-proven acute cellular renal allograft rejection. Two of the 40 patients initially selected for the protocol were considered to be nonevaluable. Analysis of the remaining 38 patients receiving both living related and cadaveric donor allografts revealed a patient survival of 100% and a graft survival of 97%. Primary rejection reversal was achieved in 18/19 (95%) patients treated with T10B9.1A-31 and in 20/21 (95%) of patients receiving OKT3. The two patients who did not respond to the first mAb responded to the crossover mAb. Rerejection occurred in 3/18 (17%) of patients treated with T10B9.1A-31 and in 3/20 (15%) treated with OKT3. The mean day of rejection reversal was 1.9 +/- 0.7 with T10B9.1A-31 and 3.37 +/- 1.21 with OKT3 treatment. The rise in mean serum creatinine after mAb administration and the mean creatinine on days 1 through 6 were significantly less in patients treated with T10B9.1A-31. Biopsy specimens analyzed for rejection revealed no significant difference between the T10B9.1A-31 and OKT3 cohorts. The mean serum creatinines at 30, 60, 180, and 360 days posttransplantation were the same for both groups. Significantly fewer febrile, respiratory, and untoward effects followed the first dose (day 0) and fewer febrile, gastrointestinal, and neurological side effects occurred with subsequent doses (days 1-9) in patients treated with T10B9.1A-31. Infectious complications occurred in 3/13 patients treated only with T10B9.1A-31, in 9/17 OKT3-treated patients, and in 4/8 patients treated with both mAb. Analysis of human antimouse antibody (HAMA) revealed that the development of HAMA with T10B9.1A-31 was similar to that of OKT3.     

Induction immunosuppression for lung transplantation with OKT3

BACKGROUND: The use of OKT3, an anti-CD3 monoclonal antibody, for immunosuppressive therapy for lung transplantation has been restricted because of concerns regarding infectious risk and cardiopulmonary instability after its administration. METHODS: Fifty-two patients received OKT3 (5 mg/d intravenously for 10 days) for induction of immunosuppressive therapy, along with azathioprine (1.5 mg x kg(-1) x d(-1) intravenously) and enteral cyclosporine (12 mg x kg(-1) x d(-1)). Maintenance steroid therapy was begun on postoperative day 8. Prophylactic antifungal therapy (fluconazole or amphotericin B) and ganciclovir was used in all patients. Serial transbronchial biopsy and measurements of pulmonary function were used to assess patients for evidence of infection or rejection. Cytomegalovirus infection was diagnosed by biopsy or the presence of cytomegalovirus antigenemia. RESULTS: The 30-day mortality rate was 4%; the in-hospital mortality rate was 8%. Acute graft failure was seen in 6 patients. The median length of intubation was 5 days, and the median hospital stay was 30 days. Systemic and pulmonary artery systolic pressures, cardiac index, and ratio of arterial partial oxygen pressure to fraction of inspired oxygen showed no significant alteration after OKT3 dosage. Gram-negative pulmonary infections were identified in 12 patients. Aspergillus infection was seen in 7 patients. Cytomegalovirus infection in 8 patients responded to ganciclovir and did not affect mortality. Respiratory syncytial viral infection was seen in 7 patients. Acute rejection was never seen during OKT3 administration. No episodes of acute rejection were identified in 14 patients at any time postoperatively. In the remainder, episodes of acute rejection responded to steroid or antithymocyte globulin therapy. At a median length of follow-up of 31 months, freedom from obliterative bronchiolitis was 69%+/-9% at 36 months. The overall survival rate was 88%+/-5% at 12 months, 82%+/-6% at 24 months, and 74%+/-7% at 36 months after transplantation. CONCLUSIONS: OKT3 is a safe and effective agent for induction immunosuppressive therapy in lung transplant recipients that limits the incidence of acute rejection and may decrease the incidence of obliterative bronchiolitis.     

肝肾联合移植15例报道

目的探讨肝肾联合移植的适应证和疗效。方法对2001年2月至2003年12月施行肝肾联合移植术的15例患者进行了随访。15例中,乙型肝炎后肝硬化合并肝肾综合征8例、合并尿毒症2例、合并糖尿病肾病1例;多囊肝和多囊肾2例;Caroli病合并多囊肾1例;酒精性肝硬化合并尿毒症1例。对肝肾联合移植患者的手术方式,围手术期并发症,术后急、慢性排斥反应和乙型肝炎复发情况及随访结果进行了分析。结果15例肝肾联合移植术后移植物功能均恢复良好,6个月和1年生存率为100%。1例术前有严重营养不良者,术后给与48d的呼吸机支持后康复。术后创面出血和消化道出血各1例,经非手术治疗后治愈。胆道吻合口狭窄1例,用内镜下球囊扩张术治愈。1例术后2周发生急性移植肝排斥反应,给予激素冲击治疗后得到控制。1例术后30个月时因停用拉米夫定后乙型肝炎复发死于移植肝功能丧失。结论肝肾联合移植是终末期肝病合并慢性肾功能衰竭或肾功能损害的安全有效方法。对乙型肝炎患者术后尽早应用拉米夫定和乙型肝炎病毒免疫球蛋白预防肝炎复发。     

The effect of indomethacin on the febrile response following OKT3 therapy.

Fifty renal transplant recipients with histologically documented acute allograft rejection were treated with OKT3 monoclonal antibody therapy. Group 1 (n = 25) received standard premedication with steroids, acetaminophen, and diphenhydramine. Group 2 (n = 25) received these agents plus indomethacin in an attempt to minimize the early adverse effects associated with OKT3. At 1 hr prior to the first dose of OKT3, 50 mg of indomethacin was administered orally followed by 25 mg every 6 hr for the next 48 hr. Demographics were similar in the two groups. Reversal of rejection occurred in 23 of 25 (92%) in group 1, and in 22 of 25 (88%) in group 2. Graft survival rates at six months after the rejection were 88% in group 1 and 80% in group 2. There was a single patient death in group 2, due to a suicide in a patient with a functioning kidney and pancreas graft. The maximum temperature was significantly diminished in the group receiving indomethacin during the first three days of OKT3 therapy. The percentage of patients with a maximum temperature less than 100 degrees F was significantly higher in group 2: day 1--16% vs. 36%, day 2--12% vs. 48%, day 3--52% vs. 68% for group 1 and group 2, respectively. No serious side effects occurred in either group--however, subjective side effects were less common in group 2. Serum creatinine levels were similar in the two groups prior to rejection, at the start of OKT3 therapy, at the peak during OKT3 therapy, at the end of OKT3 therapy, and 30 days and 180 days post OKT3. The data indicate that the concurrent use of indomethacin with OKT3 appears to significantly decrease the initial febrile response without compromising renal function or the efficacy of OKT3 therapy.     

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.     

Efficacy of OKT3 retreatment for refractory cardiac allograft rejection

Although OKT3 monoclonal antibody is a useful therapy for refractory cardiac allograft rejection, the use of OKT3 for prophylaxis may be limited by the potential of sensitization and subsequent loss of efficacy on retreatment. OKT3 was required for refractory rejection in 21 of 165 recipients transplanted between March 1985 and August 1988. Twelve of these patients had previously been exposed to OKT3, and the retreatment efficacy was evaluated. The study population averaged 42.1 +/- 15.3 years of age (mean +/- SEM) and had experienced 2 +/- 1 previous episodes of rejection. The prior episodes of rejection had been treated with pulse methylprednisolone and antithymocyte globulin, and in addition 3 patients (25%) also required a course of antilymphoblast globulin. Retreatment OKT3 for refractory rejection was required 120 +/- 94 days following transplantation. CD3+ lymphocytes were eliminated from the circulation within 24-48 hr in 11 of 12 patients, all of whom showed histologic improvement within the first week. Total resolution on the initial follow-up biopsy was noted in 9 (75%) during the course of therapy. Subsequent rejection episodes occurred in 9 (82%) of the survivors at 71 +/- 64 days. One-year survival was 83% in this vigorously rejecting patient population. Serious infections occurred within 3 months of therapy in 4 (36%). The side effects of OKT3 retreatment were similar to those seen with first exposure and did not require OKT3 discontinuation. Thus OKT3 may be administered with success in most patients who have previously been exposed to it.     

Mycophenolatemofetil for immunosuppression after liver transplantation: a follow-up study of 191 patients

BACKGROUND: Mycophenolatemofetil (MMF) combined with calcineurin inhibitors (CNIs) as immunosuppression after orthotopic liver transplantation (OLT) is still under discussion. We retrospectively investigated the immunosuppressive potency of MMF for treatment of steroid-resistant acute rejection (AR) or chronic rejection (CR), chronic graft dysfunction, and CNI-induced toxicity in patients after OLT. METHODS: Between 1988 and 2001 we performed 1386 OLTs in 1258 patients. Since 1995, 191 patients have received MMF after OLT for steroid-resistant AR or CR, chronic graft dysfunction (115 patients), and CNI-induced toxicity (76 patients). The mean follow-up time was 56 months. RESULTS: Of 47 patients with steroid-resistant AR, 12 had been treated with OKT3, without resolving the rejection. Overall, bilirubin and transaminases decreased significantly within 2 weeks after the addition of MMF, and liver function normalized in 38 patients. Five of eight patients with CR demonstrated stable liver function after a follow-up of 55+/-8 months; 52 of 60 patients with chronic graft dysfunction improved within 3 months; and 46 of 59 patients with CNI-induced nephrotoxicity improved after MMF treatment and a reduction of CNIs (with a significant decrease in serum creatinine within 2 weeks and an increase of creatinine clearance within 3 months). Clinical symptoms improved in 10 of 12 patients with neurotoxicity and four of five patients with hepatotoxicity. Side effects of MMF, such as gastrointestinal disorders or bone marrow toxicity, occurred in 60 patients (31.4%). The incidence of infections did not increase. Patient survival was 93%, and graft survival was 88.2%. CONCLUSIONS: MMF is a potent and safe immunosuppressive agent in OLT recipients for rescue therapy in AR, CR, or chronic graft dysfunction and helps to reduce the serious toxic side effects of CNIs.     

Long-term outcome of the use of OKT3 to treat steroid-resistant acute renal allograft rejection

OKT3 was used to treat steroid-resistant acute renal allograft refection in 30 of 496 adult patients transplanted over a 6-year period. Rejection was reversed (defined as a fall in serum creatinine by 50% or more within 30 days of treatment with OKT3) in 40% of cases. Successful reversal was significantly more likely when rejection occurred shortly after transplantation (t ratio-2.53; P=0.019). The long-term outcome was disappointing; the actuarial graft survival at 1 year from the start of treatment with OKT3 was 42%, and no grafts have thus far survived longer than 3 years. Graft survival was horter in older patients (coefficient/standard error 2.226; P<0.05), and no other predictor of long-term outcome was identified. Patient survival at 3 years was 88%. Serious infection occurred in 33% of patients, with two deaths. Our experience suggests that treatment with OKT3 is unlikely to reverse acute renal allograft rejection in more than half of patients where rejection is resistant to steroids. Although long-term graft survival occurred in a few cases, the overall long-term outcome was disappointing, particularly in older patients. Finally, our analysis indicates the difficulty of predicting which patients will derive long-term benefit when OKT3 is used to treat steroidresistant rejection.