OKT3 Induction Therapy Research Articles

Lymphomas in Heart Transplant Recipients: Do Antivirals Protect Against the Neoplastic Effect of Anti-CD3 Monoclonal Antibody?

Introduction and Aim After cardiac allograft vasculopathy, tumors are the second leading cause of death among heart transplantation (HT) patients after the first year. Lymphomas are tumors of lymphocytic origin whose development has been associated with the use of anti-CD3 monoclonal antibody (OKT3). Some studies suggest that the use of acyclovir could counteract this effect. Our aim was to investigate the impact of gancyclovir on OKT3 and lymphoma development after HT. Materials and Methods We included all 239 HTs performed in our center from 1989 to 2002. We divided patients into those who received gancyclovir treatment (prophylaxis, pre-emptive therapy, or for cytomegalovirus infection) versus those who did not receive this agent at any time during follow-up (88 vs 151 patients). The statistical methods were Student's t and chi-square tests. Results There were no differences in the baseline characteristics of the patients—gender, recipient age, etiology leading to HT, diabetes, and dyslipidemia—except for a higher rate of hypertension among the group who did not receive gancyclovir (73.7 vs 60.2%; P = .03). None of the 7 patients who developed lymphomas during the follow-up received gancyclovir (0 vs 4.6%; P = .040). Conclusions Antivirals may have a relevant role to neutralize potential neoplastic effects (especially lymphomas) associated with the use of OKT3 induction therapy.

Efficacy of a Negative Conversion Trial and Subsequent Living Donor Kidney Transplant Outcome in Recipients with a Positive Lymphocyte Crossmatch

Background: Patients with a positive lymphocyte crossmatch (LCX) do not undergo kidney transplantation. In such patients, a negative conversion protocol consisting of intravenous immunoglobulin (IVIG), plasmapheresis, and potent immunosuppressant is one of the options for transplantation. Methods: 14 patients who showed a positive LCX with living donors underwent a trial of negative conversion between January 2002 and July 2007. Plasmapheresis was performed every other day, up to 6 times maximum. IVIG was infused after plasmapheresis, with a total dose of 500 mg/kg divided over 6 days. Kidney transplantation was performed immediately after negative conversion. Anti-thymocyte globulin (ATG) or OKT3 induction therapy was used with the combination of tacrolimus, mycophenolate mofetil, and prednisone in the perioperative period. Results: Negative conversion of LCX was achieved in 13 of 14 patients (92.9%). Transplantations were performed successfully in these 13 patients without hyperacute rejection. Four recipients developed acute rejection, which was well controlled by steroid pulse therapy. During the follow-up periods of 45.4 ± 22.0 months, all recipients except 1 showed excellent graft function. Conclusion: Selected patients with a positive LCX can undergo successful transplantation using plasmapheresis, IVIG, and potent immunosuppressants. Recipients with negative conversion of LCX showed acceptable posttransplant results.

A randomized multicenter trial of OKT3 mAbs induction compared with intravenous cyclosporine in pediatric renal transplantation

Acute rejection leading to renal graft failure is more frequent among children. In patients treated with T cell antibody induction, retrospective data from the pediatric registry show a 22% reduction in the risk of graft failure. We conducted a randomized trial (n = 287) using OKT3 mAbs in one (OKT3) arm and intravenous cyclosporine in the other arm (CYS). Maintenance therapy consisted of randomized, double blind Sandimmune or Neoral together with prednisone and either azathioprine (AZA) or mycophenolate mofetil (MMF). Morbidity, mortality, rejection rates and adverse reactions in the two study arms were similar. Through 4 yr, graft failure was 27% in OKT3 and 19% in CYS (p = 0.15). One-year graft survival was 89.1% in OKT3 and 89.2% in CYS (p = .19). In multivariate analysis, OKT3 had a numerically inferior graft survival (RR = 1.4, CI 0.8-2.2, p = 0.22). In OKT3 graft survival was inferior for children aged 6 yr or younger. Our trial demonstrates that the incidence of acute rejection or graft failure in pediatric patients is not improved by OKT3 induction therapy relative to cyclosporine induction.

Lung transplantation: A decade of experience

Background Over the past 3 decades, the field of lung transplantation has been refined. However, many barriers exist that limit long-term success. The purpose of this study was to review a single institution’s long-term experience with single and double lung transplantation and to assess the effect of different immunosuppressive therapies on outcomes. Methods Lung transplant recipients, both single and double, were reviewed, retrospectively. Patients were divided into five groups: group I, all lung transplants ( n = 127); group II, single lung transplants ( n = 73); group III, double lung transplants ( n = 54); group IV, OKT3 induction therapy recipients ( n = 27); and group V, RATG induction therapy recipients ( n = 100). Rates of survival, rejection, bronchiolitis obliterans syndrome (BOS) and infection were analyzed at 1, 3, and 5 years. Results There were no significant differences in survival, acute rejection rate, freedom from BOS, nor infection between single and double lung transplant recipients. Induction therapy with RATG (group V) was associated with significantly improved survival and freedom from acute rejection, BOS, and infection when compared to OKT3 induction therapy (group IV). Conclusions An earlier impression that RATG is superior to OKT3 induction therapy has borne true in terms of overall survival and incidence of BOS, acute rejection and infection rates. Lung transplantation, using RATG induction therapy, remains an important modality for end-stage pulmonary disease.

FAVORABLE LONG TERM RESULTS WITH THYMOGLOBULIN (RATG) INDUCTION IN PANCREAS TRANSPLANTATION

P411 Aims: Induction therapy with RATG is effective in preventing acute rejection in pancreas transplantation and has replaced OKT3 for induction therapy at most centers. T-cell depletion is more prolonged with RATG than OKT3 and the long-term effects of this have not been fully studied. We changed our pancreas protocol in 6/99 with the availability of RATG. In this study, we evaluate the 3-year outcomes (rejection rates, graft survival, patient survival, current maintenance immunosuppressive therapy) of pancreas transplant recipients who received RATG induction therapy and compare them to pancreas transplant recipients who received OKT3 induction therapy. Methods: A retrospective, single-center analysis was preformed of 37 pancreas transplant recipients who received RATG induction therapy between 6/99 and 12/99 compared to 52 pancreas transplant who received OKT3 induction between 1/98 and 6/99. All patients received tacrolimus (FK506), mycophenolate mofetil (MMF) and prednisone maintenance therapy. Median follow-up was no different between groups (4.18±1.3 yrs RATG vs. 4.67±1.7 yrs. OKT3). Results: Rejection rates (RR) and graft survival were similar in both groups at 1-year and 3-year post-transplant. Rejections occurring after 1-year post-transplant in the RATG-group were mostly (43%) due to noncompliance. Mean doses of FK506, MMF and prednisone were not significantly different between groups at 1-,2- or 3-year post transplant. FK506 levels were significantly higher at 1-year post transplant in the OKT3 group (13.1±4.6 ng/mL OKT3 vs. 10.5±3.4 ng/mL RATG, p=0.01) but were no different at 2- or 3-yrs. post-transplant. Mean ± Standard Deviation The average cost of a 7-day course of RATG therapy ($3873) in this study was lower than the cost of OKT3 therapy at an average dose of 35 mg/10 days ($4200) not including the cost of CD3 monitoring. The median length of stay (LOS) for the initial hospitalization was 10±1.5 days in the RATG group compared to 12±1.6 days in the OKT3 group (p=0.32). CMV infections occurred in 13.5% of RATG-induced patients compared to 19.2% of OKT3-induced patients (p=0.48). Conclusions: Pancreas transplants receiving RATG induction therapy with FK506, MMF and prednisone maintenance immunosuppression experienced comparable outcomes to those treated with OKT3 induction therapy with no increase in CMV infections. RATG induction therapy was less expensive than OKT3 with a decreased median LOS in the RATG group.FigureFigure

Evidence-based immunosuppression after pediatric renal transplantation—A dream?

IT IS INCREASINGLY evident that only prospective, randomized controlled clinical trials provide the highest level of evidence to compare therapeutic regimens. Clinical trials provide the framework to search for more effective and less toxic immunosuppressive agents to control solid organ transplant rejection. While systematic reviews have been presented on immunosuppression after solid organ transplantation in adults, the pediatric literature on randomized controlled clinical trials remains extremely scarce. Most trials have evaluated the safety and efficacy of recombinant human growth hormone after pediatric renal transplantation. In a relatively small trial after pediatric liver transplantation, two antihypertensive agents were compared in addition to a cyclosporine-based immunosuppressive protocol. Large-scale randomized controlled clinical trials have been few until recently. There was one trial comparing the efficacy and safety of prophylactic treatment with OKT3 monoclonal antibody versus antilymphocyte globulin induction therapy after pediatric renal transplantation. There have been several large-scale, randomized, multicenter trials in adult renal transplant recipients comparing the clinical efficacy and safety of both calcineurin inhibitors, combined with azathioprine and corticosteroids as adjunctive therapies. Acute allograft rejection was significantly reduced with tacrolimus compared with cyclosporine-based immunosuppressive therapy. There is only one similar trial in children. However, there also is a large randomized controlled trial in the United States comparing OKT3 induction therapy with IV cyclosporine. This trial has not yet been published. The aim of this manuscript is to review the existing trials to find explanations for the lack of development but obvious need for such trials in pediatric solid organ transplantation.

No long-term benefit of low-dose OKT3 induction therapy in non to moderately immunized renal allograft recipients

No long-term benefit of low-dose OKT3 induction therapy in non to moderately immunized renal allograft recipients

Rabbit antithymocyte globulin versus OKT3 induction therapy after heart-lung and lung transplantation: effect on survival, rejection, infection, and obliterative bronchiolitis

Rabbit antithymocyte globulin versus OKT3 induction therapy after heart-lung and lung transplantation: effect on survival, rejection, infection, and obliterative bronchiolitis

ATGAM Versus OKT3 Induction Therapy in Cadaveric Kidney Transplantation: Patient and Graft Survival, CD3 Subset, Infection, and Cost Analysis

ATGAM Versus OKT3 Induction Therapy in Cadaveric Kidney Transplantation: Patient and Graft Survival, CD3 Subset, Infection, and Cost Analysis

Long-Term Outcome With the Use of OKT3 Induction Therapy in Heart Transplant Patients: A Single-Center Experience

Long-Term Outcome With the Use of OKT3 Induction Therapy in Heart Transplant Patients: A Single-Center Experience

RECOMBINANT HUMAN TUMOR NECROSIS FACTOR RECEPTOR Fc FUSION PROTEIN(TNFR:Fc) THERAPY IN KIDNEY TRANSPLANT RECIPIENTS RECEIVING OKT3 INDUCTION THERAPY

294 The monoclonal antibody OKT3 is widely used for induction and treatment of rejection in organ transplant recipients. However, initial doses of the drug are often associated with a cytokine-induced acute clinical syndrome (ACS), which appears to be primarily mediated by TNFα. Several approaches have been used to minimize OKT3-ACS symptoms including pretreatment with corticosteroids, IL-10, and anti-TNF monoclonal antibodies. This study examined the safety of a recombinant human TNF receptor Fc fusion protein(TNFR:Fc) administered post-operatively to kidney transplant recipients, and the ability of the drug to reduce OKT3-ACS symptoms. Methods: Sixteen renal allograft recipients undergoing OKT3 induction therapy were randomized into 4 groups of 4 patients each. All patients received intraoperatively IV azathioprine (Imuran) 3 mg/kg and methylprednisolone 3 mg/kg 1 hour prior to 2.5 mg IV OKT3. Daily IV dosing of 2.5 mg OKT3 was continued for 12 days and CsA was initiated when serum creatinine ≤3.0. The 3 treatment groups received TNFR:Fc (4, 8, or 16 mg/m2) 1 hour prior to OKT3 administration on days 0 and 3. ACS symptoms were assessed on post-transplant days 1 to 3 using a scoring system. Serum cytokine levels(IL-2, IL-4, IL-6, IFNγ, GM-CSF, endothelin-1, NO) were determined using ELISA, RIA, and colorimetry. Serum creatinine and C-reactive protein (CRP) levels were also followed. Results: For most parameters tested there were no differences between groups. Noteworthy findings are summarized:TableThe etiology of the higher incidence of infection in treated patients was unclear. The infections were minor, resolved, and typical of the patient population. The small size of the study and confounding factors such as gender and transplant type (cadaveric vs. living) likely contributed to the observed difference. There were no other differences in adverse event profiles between the two groups. Conclusion: This study suggests that TNFR:Fc is well tolerated by renal transplant patients receiving OKT3 induction therapy. TNFR:Fc therapy may offer some improvement in symptoms associated with OKT3-ACS. Considering the evidence implicating TNFα in the pathogenesis of acute rejection. TNFR:Fc may be a useful adjuvant immunomodulator in the subacute period (1 to 6 months) following transplant, allowing a reduction or earlier withdrawal of steroids.

OKT3 induction therapy and cadaveric renal transplantation in black patients

OKT3 induction therapy and cadaveric renal transplantation in black patients

Improved Survival of En Bloc Renal Allografts from Pediatric Donors

Purpose We developed a technical and immunological protocol to increase survival of renal transplants from pediatric donors. Materials and Methods En bloc kidneys (22) were procured from donors weighing 2 to 14 kg. (1 to 60 months old) and transplanted into adult recipients. In group 1 (12 patients) sequential therapy was used for kidneys with more than 35 hours of cold storage and immediate triple therapy (cyclosporine, azathioprine and prednisone) was used for those with less than 35 hours of cold storage. In group 2 (10 patients) OKT3 induction therapy was used. Mean followup was 4.7 years. Results Mean blood pressure at 1 and 4 years was not significantly different between the groups. Mean serum creatinine was not significantly different between the groups at 1 year but it was significantly less in group 2 at 4 years (1.9 +/− versus 1.2 +/− 0.24 mg./dl., p <0.05). At 1 year of followup the complication rate was 75% in 9 of 12 patients in group 1, including 4 infections or leaks (2 lost), 6 rejections (3 lost) and 3 cases of thrombosis or hemorrhage, and 20% (p <0.01) in group 2 (1 patient had the hemolytic uremic syndrome leading to graft loss). Graft survival was significantly greater in group 2 at all 4 years of followup (p = 0.05). Conclusions The success of pediatric en bloc renal transplantation can be enhanced by induction therapy in healthy recipients.

OKT3 induction therapy: influence of duration on rejections and infections

OKT3 induction therapy: influence of duration on rejections and infections

A cost-effectiveness analysis of okt3 induction therapy in cadaveric kidney transplantation

We evaluated the cost-effectiveness of a standard immunosuppressive regimen versus an OKT3 induction regimen in cadaveric kidney transplant recipients. Cost estimates were based on results from a five-center randomized trial comparing the safety and efficacy of OKT3 induction with a conventional triple-drug regimen and financial data from the National Cooperative Transplantation Study, the Medicare Provider and Analysis Review database, and other sources. Patients received OKT3 (5 mg/day) by intravenous (IV) bolus injection for 10 to 14 consecutive days in conjunction with azathioprine, prednisone, and the delayed addition of cyclosporine (CsA) on day 11 (n = 105) or a conventional immunosuppressive regimen consisting of CsA, azathioprine, and prednisone (n = 102). The following measures were used to evaluate the two regimens: costs incurred between transplantation and graft failure; the effectiveness of the two regimens as defined by length of graft survival; and cost-effectiveness ratios through 5 years of observed follow-up and modeled through the expected duration of graft survival. Results showed that OKT3 induction uniformly adds $8,219 to the cost of the transplant hospitalization. However, most of this cost is offset by a reduction in the cost of treating rejection episodes in the OKT3 group ( P = 0.002). A trend toward improved graft survival was detected in the OKT3 group ( P = 0.158). Through 5 years of observed follow-up, costs per year of graft survival are $30,474 with OKT3 versus $32,687 with the conventional regimen. Modeled through the expected duration of graft survival, OKT3 induction costs $8,335 for each additional year of graft survival. Results are fairly insensitive to wide variations in baseline assumptions. We conclude that OKT3 induction improves the cost-effectiveness of kidney transplantation.

Influence of donor-recipient HLA-DR mismatches and OKT3 prophylaxis on cadaver kidney graft survival.

Previous studies from our center have shown that donor-recipient HLA-DR mismatches (MM), characterized by the presence of the DR antigen in the donor but not in the recipient or vice versa, are associated with differential effects on graft survival (GS): some of them are beneficial (BEN) with results similar to those of HLA-DR identical or compatible pairs (85% 18 months GS) and some are detrimental (DET) (64% 18 months GS), whereas the other MM, neither BEN nor DET (neutral [NEU]) yield intermediate results (78% 18 months GS). The aim of the present study was to update the results at a longer follow-up time and to assess whether they are influenced or not by prophylactic administration of anti-CD3 mAb (OKT3). The analysis of 234 transplantations performed from 1980 to 1994 with only 1 HLA-DR MM confirmed the BEN effects of HLA-DR5 in either the donor or the recipient and the DET effects of HLA-DR1 or -DR2 in the donor and of HLA-DR2 or -DRW6 in the recipient. These effects were independent of those exerted by other, HLA-DR not related, prognostic factors. The transplants with 1 HLA-DR MM were then compared with those with zero HLA-DR MM (n = 378) and 4 groups were formed according to 2 levels of HLA-DR MM (zero or BEN MM vs. NEU or DET MM) and immunosuppression (with vs. without OKT3 prophylaxis). GS at 5 years was 63% in the group with either zero or BEN MM as compared with 41% in the group with either NEU or DET MM in the absence of OKT3 prophylaxis (P < 0.02); in comparison, with OKT3 prophylaxis, GS at 5 years was 73% in the group with either zero or BEN MM as compared with 58% in the group with either NEU or DET MM (P = 0.07). We conclude that the differential effects of HLA-DR MM on GS are still observed under OKT3 prophylaxis, that the effects of HLA-DR and immunosuppression on graft outcome are additive, and that OKT3 induction therapy is superior to therapy without OKT3. These observations could have important implications for the allocation policy and management of renal transplants.

The incidence of interstitial and vascular kidney rejection after pancreas-kidney transplantation.

Several groups have reported that recipients of a simultaneous pancreas-kidney transplantation suffer from more kidney rejection episodes than do recipients of a kidney transplantation (1-6). However, it is not known whether this is interstitial rejection, vascular rejection, or both. In this study, the renal biopsies and transplantectomies of 45 pancreas-kidney and 48 kidney transplant recipients were evaluated for the presence of interstitial and vascular rejection. Furthermore, the influence of OKT3 induction therapy on rejection after pancreas-kidney transplantation was studied. Of the 45 pancreas-kidney recipients. 4 patients did not suffer from rejection during follow-up, 28 suffered only from interstitial rejection, and 13 suffered from vascular (with or without interstitial) rejection, whereas 12, 19, and 14 of the 48 kidney transplant patients had no rejection, interstitial rejection, or vascular (with or without interstitial) rejection, respectively. Three patients with a kidney transplant were treated for rejection although no biopsy was taken. In the pancreas-kidney group, 38 of the total of 149 biopsies and transplantectomies taken contained no rejection, 92 had interstitial rejection, and 19 had vascular rejection. In the kidney group, these values were 13, 41, and 25, respectively, of 79 biopsies and transplantectomies taken (P = 0.002). Five-year renal graft survival was 79% in the kidney group and 60% in the pancreas-kidney group. Renal graft survival rates differed significantly (P = 0.02). Renal graft survival and occurrence of rejection did not reach significance between pancreas-kidney recipients treated with OKT3 induction therapy and pancreas-kidney recipients receiving conventional triple therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute vascular (humoral) rejection in non-OKT3-treated cardiac transplants

To determine the incidence and morphologic features of acute vascular rejection (AVR) in cardiac transplant patients who have not received OKT3 induction therapy, we performed immunofluorescence (IF) staining for Clq and C3c on 341 endomyocardial biopsies from 135 patients. Each AVR biopsy, defined by positive IF, was further evaluated for C4c, C5, IgG, IgM, and IgA. Light and electron microscopy were also performed. The clinical features of each case were reviewed. A total of 29 biopsies from 6 recently transplanted patients (1993) and 10 biopsies from 4 long-term transplants (pre-1993) had IF evidence of AVR. All patients with AVR had linear vascular deposits of various complement components and immunoglobulins. Of the 6 recently transplanted patients, 4 were multiparous females. The male had a single episode of AVR. IF patterns were variable between and within patients. Clq and C3c were the most consistently detected complement components. IgM was the most frequently detected antibody. Of the 10 cases of AVR, 6 occurred within the first month post-transplant. Myocyte necrosis was present in all cases with cardiac dysfunction. Patients with early onset AVR had more recurrences and one fatality. There was one fatality in the long-term transplant group. Concomitant grades 0 to 4+ cellular rejection did not correlate with results of IF or clinical severity. The incidence of AVR in non-OKT3-treated patients is 7%. Of the early onset patients, 66% are multiparous females, indicating the possible importance of prior sensitization. IF patterns are not predictive of outcome. AVR may be asymptomatic, but early onset predicts a difficult clinical course and is detected only by IF screening.

Randomized double-blind study of standard versus low-dose OKT3 induction therapy in renal allograft recipients

A double-blind, randomized, prospective study was undertaken to determine if the dose of OKT3 used for induction immunosuppression following kidney and kidney-pancreas transplantation affected clinical outcomes. Twenty-five patients were randomized in each group. Five patients in each group received a combined kidney/pancreas transplant. All patients received sequential quadruple immune suppression (azathioprine and methylprednisolone, followed by oral prednisone and cyclosporine A), regardless of randomization to the standard (5 mg) or low-dose (2 mg) OKT3 group. OKT3 was administered for 7 to 14 days. The dose of OKT3 was adjusted to ascertain the clearance of peripheral positive CD3 lymphocytes. The mean cumulative OKT3 dose for the standard dose group was 52.0 mg versus 23.4 mg for the low-dose group (P

Low-dose OKT3 induction therapy following renal transplantation: a controlled study

In a prospective clinical study we tested the immunosuppressive properties and toxicity of low-dose OKT3 induction therapy in renal transplant recipients. 50 consecutive renal transplant recipients were alternatingly assigned to low-dose OKT3 induction or prednisolone/cyclosporin. Low-dose OKT3 induction treatment consisted of 0.5 mg OKT3 twice daily for 10 days, initially combined with azathioprine and prednisolone maintenance immunosuppression that was converted to prednisolone/cyclosporin at the end of the course. During a 15-29-month follow-up period, low-dose OKT3 induction therapy was found to reduce significantly the incidence of acute rejections, as compared to the usual prednisolone/cyclosporin maintenance immunosuppression (21 versus 52%, P = 0.02). There also was a tendency towards an improved graft function after low-dose OKT3, although no significance was reached. Furthermore, compared to a historical control group of renal transplant patients in whom acute rejection was treated with 5 mg OKT3 daily, low-dose OKT3 appeared to cause fewer side-effects. We conclude that low-dose OKT3 induction therapy is superior to prednisolone/cyclosporin in preventing acute rejection after renal transplantation and that it is better tolerated than conventional OKT3 treatment.