Treatment with OKT3 and cyclosporine for acute allograft rejection

In summary, we believe that our experience with concomitant use of OKT3 and either reduced-dose CyA for treatment of renal allograft rejections or full-dose CyA therapy for treatment of liver allograft rejection is both safe and possibly more effective in reversing allograft rejection than use of the antibody alone. This strategy has also allowed us to use this MAb therapy without incurring the untoward consequence of the development of hightiter anti-OKT3 antibodies that could preclude its subsequent reuse.     

Medium-term results of extracorporeal membrane oxygenation for severe acute lung injury after lung transplantation.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has been used successfully for early, severe reperfusion injury after lung transplantation. The purposes of this study are to: (1) document the medium-term survival of patients treated with ECMO; and (2) assess the extent of recovery of their pulmonary function. METHODS: We retrospectively reviewed charts of 172 patients having lung transplants at our institution from 1997 through 2002. The group included 16 patients (9% of total; 10 bilateral, 5 single, 1 living lobar) treated with ECMO for primary allograft failure after single or bilateral single-lung transplantation. Survival and bronchiolitis obliterans syndrome (BOS)-free survival rates were calculated. Pulmonary function was assessed at 2 months, 1 year and 2 years post-transplant. RESULTS: Median hospital stay was 48 days for the ECMO group and 16 days for the overall group (p < 0.05). The 90-day survival was 60% in the ECMO group, and 90% in the overall group. The 2-year survival was 46% in the ECMO group, and 69% in the overall group. Mean forced expiratory volume in 1 second (FEV(1)) in the ECMO group at 1 year was 59 +/- 13% of predicted, and at 2 years 60 +/- 15% of predicted; it was not significantly different for the overall group. CONCLUSIONS: Patients treated with ECMO for primary allograft failure after lung transplantation showed acceptable medium-term survival and pulmonary function.     

Successful retreatment of allograft rejection with OKT3

OKT3 is a murine monoclonal antibody to the CD3 antigen of human T lymphocytes. The production of human antimurine antibodies after treatment with OKT3 has been perceived as a major limitation to its extended use and reuse. Treatment of 142 patients with 168 courses of OKT3 resulted in the development of antimouse antibody in 28% of the patients. Twenty-six patients (16 kidney, 6 liver, 3 heart, 1 pancreas) have been retreated with 27 courses of OKT3. Eighteen patients had no antimurine antibodies present, and the rejection reversal rate was 83% (15/18). Six patients had a low-titer antimurine antibody present, and rejection reversal occurred in 5 (83%). Rejection was not reversed in 2 patients with a high-titer antibody. Development of antimurine antibody was more frequent in renal transplant recipients (33%) than in hepatic (12%) or cardiac transplant recipients (18%). We believe that this reflects the fact that concomitant immunosuppressive therapy is more likely to be reduced during OKT3 therapy in renal transplant recipients than in hepatic or cardiac transplant recipients. Retreatment of patients with no anti-OKT3 antibody resulted in depletion of CD3+ cells from the peripheral blood, but it took longer than in patients being treated with OKT3 for the first time. Similarly, serum OKT3 levels rose more slowly in retreated patients compared to first treatment. In retreating patients with a low-titer antimurine antibody, it often was necessary to increase the dose of OKT3 in order to achieve adequate serum OKT3 levels and to deplete CD3+ cells. De novo antimurine antibody developed in 4 of the 18 (22%) antibody-negative patients who were retreated. In conclusion, retreatment with OKT3 should not be considered unless the antibody status of the patient is known. Development of low-titer antibodies does not preclude successful retreatment with OKT3; however, alternate antirejection therapy should be used in patients with high-titer antimurine responses.     

Prediction of successful allograft rejection retreatment with OKT3.

OKT3 is considered to be effective in the prophylaxis and treatment of rejection. However, anti-OKT3 immunization is still a major side-effect. Only the IgG antiidiotypic component of the response is responsible for neutralization of OKT3 therapeutic activity by inhibiting OKT3's binding to T cells (i.e., blocking antibodies). It has recently been reported that successful OKT3 retreatment could be performed in patients showing circulating anti-OKT3 antibodies assessed by ELISA, which does not distinguish between blocking and nonblocking antibodies. The aim of this study was to investigate the role of these two types of anti-OKT3 antibodies for their capacity to interfere with effective OKT3 retreatment. Twelve cadaver renal allograft recipients who received OKT3 inducing therapy, were given a second 10 day-course of OKT3 for treatment of rejection. Circulating CD3+ cells were sequentially monitored. Anti-OKT3 antibodies were detected by using both conventional ELISA and an immunofluorescence inhibition test specifically detecting blocking antibodies. OKT3 and the patient's serum were incubated for 30 min at 4 degrees C, and 2 x 10(5) normal T cells were added (30 min at 4 degrees C). After washing, the cells were incubated with FITC goat antimouse antiserum. Fluorescent cells were counted using a FACS analyzer. In 10 patients, at the end of the 10-day second course, less than 10% circulating CD3+ cells were detected. None of these patients had detectable antibodies in the IF inhibition assay at the beginning of retreatment, irrespective of anti-OKT3 antibody titers detected by ELISA. In contrast, in two patients, OKT3 therapy was ineffective: more than 50% circulating CD3+ cells were detected and OKT3 treatment had to be interrupted soon after it was initiated. In both of them, blocking antibodies were detected by the IF-inhibition assay. These results suggest that specific detection of blocking antiidiotypic antibodies by the IF inhibition assay is a reliable parameter for predicting the feasibility of OKT3 retreatment, avoiding misuse of this expensive therapy.     

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.     

OKT3治疗移植肾难治性排斥反应

为了解ＯＫＴ３对移植肾难治性排斥反应的治疗效果，１９９３年１月至１９９６年６月，我们对４４例肾移植术后移植肾难治性排斥反应（其中加速性排斥反应７例，急性排斥反应３７例）应用ＯＫＴ３治疗。结果：６例加速性排斥反应及３１例急性排斥反应逆转，总逆转率为８４．６％。２５例对ＯＫＴ３治疗产生迅速反应，平均逆转时间为７±４天，１２例发生延迟性反应，平均逆转时间为３４±３天（Ｐ＜０．０１）。作者认为：ＯＫＴ３治疗难治性排斥反应效果显著。巨细胞病毒感染及细胞因子释放综合征是ＯＫＴ３治疗的主要副作用。患者对ＯＫＴ３治疗的延迟性反应与细胞因子释放综合征及排斥损害有关。产生低滴度抗ＯＫＴ３抗体的患者可再次接受ＯＫＴ３治疗。     

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.     

Institutional experience with extracorporeal membrane oxygenation in lung transplantation.

Background: Extracorporeal membrane oxygenation (ECMO) is currently accepted in lung transplantation either to bridge patients to transplantation or to treat postoperatively arising severe primary graft failure. Based on promising initial experiences we have since 2001 implemented ECMO as the standard of intraoperative extracorporeal support in lung transplantation (LuTX) patients with haemodynamic or respiratory instability with the potential to prolong ECMO support into the perioperative period. The aim of this paper is to summarise our total experience with the use of ECMO in LuTX. Methods: We retrospectively reviewed all 306 patients undergoing primary lung transplantation from 1/2001 to 1/2006 with regard to the different forms of ECMO use. Results of all patients requiring ECMO were compared to those without ECMO during the observation period. Results: ECMO was used in 147 patients in total. Two patients were bridged to transplantation. A total of 130 patients received intraoperative ECMO support. In 51 of these patients ECMO was prolonged into the perioperative period. Five of these patients required ECMO support again in the postoperative period due to graft dysfunction. Contrary cardiopulmonary bypass was used in 27 patients mainly with concomitant cardiac defects. Eleven of these patients needed therapeutic ECMO in the further course. A total of 149 patients without relevant risk factors were transplanted without any intraoperative extracorporeal support. Six of these patients required ECMO support in the postoperative period for treatment of primary graft dysfunction. Overall 3-month, 1-year and 3-year survival rates were 88.6%, 82.1% and 74.63%. The mentioned survival rates were 85.4%, 74.2% and 67.6% in the intraoperative+/-prolonged ECMO group; 93.5%, 91.9% and 86.5% in the no support group and 74.0%, 65.9% and 57.7% in the CPB group. Conclusion: ECMO is a valuable tool in lung transplantation providing the potential to bridge patients to transplantation, to replace CPB with at least equal results and to overcome severe postoperative complications. Favourable survival rates can be achieved despite the fact that ECMO is used in the more complex patient population undergoing lung transplantation as well as to overcome already established severe complications.     

Increase of sTNF receptor levels in acute renal allograft rejection after treatment with OKT3

The use of OKT3 is associated with severe clinical side-effects.Adverse reactions are partly attributed to release of tumournecrosis factor (TNF). TNF binds to two receptors on the outermembranes of most human cell lines. Shedding of these proteins(sTNFR-p55 and sTNFR-p75) may block biological effects of TNF.Here we show a fair correlation between serum levels of sTNFRsand renal function as measured by glomerular filtration rate(GFR). In addition we assessed levels of sTNFR-p55 and sTNFRp75, corrected for reduced renal clearance, in renal allograftrejection and following treatment with OKT3. Corrected serumlevels (CSL) of sTNFR-p55 and sTNFR-p75 were determined in 12renal allograft patients treated for an acute rejection episodewith either OKT3 or methylprednisolone (MPNS). Serum levelsof CSLsTNFR-p55 and CSLsTNFR-p75 in both groups prior to anti-rejectiontreatment were not elevated. CSLsTNFRs peaked at 1 h after theadministration of OKT3, whereas in the MPNS group CSLsTNFRsremained unchanged. We conclude that in acute renal transplantrejection CSLsTNFRs increase after treatment with OKT3. In spiteof high circulating sTNFRs levels all OKT3-treated patientssuffered from clinical side-effects.     

Reversal of acute glomerular renal allograft rejection: a possible effect of OKT3

A major cause of renal allograft loss is glomerulovascular rejection. This case report is about an episode of histologically proven acute glomerular rejection that was successfully reversed. Monoclonal antibody OKT3 may have been the effective agent.