OKT3 Patients Research Articles

Antithymocyte globulin use for treatment of biopsy confirmed acute rejection is associated with prolonged renal allograft survival

Antithymocyte globuline (ATG) and OKT3 have been used for treatment of severe biopsy confirmed acute renal allograft rejection (BCAR). We report results on graft and patient survival including 399 subjects diagnosed with BCAR treated with either ATG or OKT3. Multivariable analyses including Banff scores were performed following three different strategies to account for confounding variables. Fifty per cent of subjects in the OKT3 group had a functioning graft 6.3 years after diagnosis of BCAR, but 74% of ATG patients' grafts were still functioning at that time point (log rank P = 0.006). Median actual graft survival was only 4.6 years in the OKT3 subjects, but 9.5 years for ATG-treated patients (log rank P = 0.004). Multivariable analysis revealed that the risk for functional graft loss was significantly elevated in the OKT3 compared to ATG patients (HR = 1.79, 95% CI 1.06-3.02, P = 0.029). The risk for actual graft loss, counting death as event, was also significantly elevated in the OKT3 patients (HR = 1.73, 95% CI 1.09-2.74, P = 0.019). The hazard of death was not different between the groups (HR = 1.55, 95% CI 0.87-2.77, P = 0.137). These data suggest that rejecting renal allografts treated with ATG exhibit longer graft survival than OKT3 treated transplant kidneys. Causal inference, however, cannot be drawn from this associational study.

A Randomized Multicenter Comparison of Basiliximab and Muromonab (OKT3) in Heart Transplantation: SIMCOR Study

Antilymphocytic antibodies have been long used for the prevention of acute rejection early after heart transplantation (HTx), but their adverse effects have limited their widespread use. Our aim was to evaluate the safety, tolerability, and efficacy of the novel anti-CD25 antibody basiliximab (BAS) compared with muromonab (OKT3). In this multicenter study, 99 patients were randomly assigned to receive either BAS or OKT3 in the early post-HTx period. The primary endpoint was safety and tolerability. Specific safety variables were predefined for a better comparison of adverse effects. Secondary endpoints concerning anti-rejection efficacy were also evaluated. No adverse events related to study medication were found in the BAS group, whereas 23 were observed among patients receiving OKT3 (P<0.0001). The proportion of patients with predefined adverse events day 4 post-HTx was much higher with OKT3 than with BAS (43% vs. 4%; P<0.0001). Fever, acute pulmonary edema, hypotension, and other complications accounted for most of the difference. At 1-year follow-up, biopsy-proven rejection episodes grade>or=3A had occurred in 39.6% of BAS patients versus 40.4% of OKT3 patients (P=0.87). There were no differences in terms of severity and timing of acute rejection episodes. The number of infectious episodes, complications not related to study medication, and actuarial survival were similar in both groups. In this HTx study, induction therapy with BAS was safer and better tolerated than OKT3, without significant differences in efficacy outcomes.

Effect on cytokine release and graft-versus-host disease of different anti-T cell antibodies during conditioning for unrelated haematopoietic stem cell transplantation.

Three different types of anti-T cell antibody were used in patients undergoing haematopoietic stem cell transplantation (HSCT) with an HLA-A, -B and -DR compatible unrelated donor: ATG-Fresenius (ATG-F) (n = 26), Thymoglobuline (TMG) (n = 61) and OKT-3 (n = 45). The groups were comparable regarding diagnosis, stage, age, conditioning and GVHD prophylaxis, Adverse events were less frequent after ATG-F treatment. Levels of IL-2, IL-6, IFN-gamma, TNF-alpha and GM-CSF were increased after OKT-3 infusion. In multivariate analysis OKT-3 treatment (P = 0.01), G-CSF treatment (P = 0.02) and a cell dose >/=2.7 x 108/kg (P = 0.03) gave a faster engraftment. Acute GVHD grades II-IV occurred in 25% of the ATG-F patients, 12% of the TMG-patients and 43% (P < 0.001 vs TMG) of the OKT-3 patients. OKT-3 was associated with acute GVHD in multivariate analysis. TRM was 26% using TMG as compared to 43% in the OKT-3 group (P = 0.03). Patient survival at 4 years was 63%, 50% and 45% in the ATG-F, TMG and OKT-3-treated patients, respectively (NS). Relapses were 8%, 49% and 34%, respectively (ATG-F vs TMG, P = 0.03). Relapse-free survivals were 61%, 40% and 37% (NS). Among CML patients the probability of relapse was 61% in TMG-treated patients, while no patients relapsed in the other two groups. To conclude, the type of anti-T cell antibody affects GVHD and relapse after HSCT using unrelated donors.

Influence of T cell depletion method on circulating γδ T cell reconstitution and potential role in the graft-versus-leukemia effect

Our laboratory previously reported that leukemia patients who developed > or = 10% gammadelta+ T cells during the first six months after receiving an anti-TCRalphabeta T-cell-depleted (TCD) graft from a partially mismatched related donor (PMRD) had a disease-free survival (DFS) advantage. These gammadelta+ T cells were V81+CD3+CD4-CD8-CD69+HLADR+ and are cytotoxic to K562 cells. In order to determine whether the anti-alphabeta TCD regimen was associated with these findings, we compared the reconstitution of gammadelta+ T cells from patients who received TCD PMRD grafts using the anti-TCRc4 MAb TIOB9-1A31 (previously reported) with similar patients who received grafts using the anti-CD3 MAb OKT3. Increased cytotoxic Vdelta1+ T cells were seen in 10 of 43 T10B9 TCD patients compared to 7 of 100 in the OKT3 TCD group (23% versus 7%, p = 0.010). T10B9 patients with increased gammadelta+ T cells also exhibited a higher range of increased gammadelta+ T cells and the length of time the gammadelta+ T cells remained high was longer when compared to OKT3 patients. Patients with increased gammadelta+ T cells whose grafts were T-cell depleted with T10B9 showed a significant decrease in relapse (p = 0.038). Similar rates and reduction in relapse were seen in OKT3 TCD patients, although significance was not reached due to the small number of patients with increased gammadelta+ T cells. Estimated 3 year disease-free survival was significantly improved in T10B9 patients with increased gammadelta+ T cells (0.79 versus 0.31, p = 0.009), a trend also seen in OKT3 patients (p = 0.091). These observations indicate that Vdelta1+CD4-CD8-cytotoxic T cells are associated with lower relapse rates and improved survival, and thus may have a role in a graft-versus-leukemia effect.

T LYMPHOCYTE RESPONSES IN CHILDREN WITH SYSTEMIC LUPUS ERYTHEMATOUS (SLE). 51

Background: SLE is characterized by abnormalities in T helper and supressor cell function, possibly due to a dysfunction in the T cell receptor complex. A decreased in vitro production of IL-2 and defective proliferative responses by T lymphocytes have been shown in adult patients. Similar data are not available for children. The duration of disease is shorter in children with SLE, thus, we proposed the hypothesis that the defective proliferative responses seen in adults would not be found in children. Methods: We obtained data from 8 children with active SLE and control data from adults and age-matched children without SLE. Peripheral blood lymphocytes from patients and controls were stimulated with antibodies directed at the T cell receptor complex and costimulator molecules. Four sets of data were obtained using the following antibodies: 1) anti-CD3(OKT3), which directly stimulates the T cell receptor complex, 2) anti-CD3 with IL-2, used to correct an IL-2 defect that was found previously in adults, 3) OKT3+anti-CD28(9.3) to stabilize the mRNA for IL-2, 4) OKT3+anti-CD45(9.4), a factor which plays a role in signal transduction. We also performed reverse transcriptase/PCR to determine if mRNA for IL-2 was being made in all of the above groups. Results: No significant differences were found between the patients (PT) and the controls(Cont). (BL PT=3172±1997, Cont=3269±1702; OKT3 PT=188305±132548, Cont=125644±78520; OKT3+IL-2 PT=258636±51591, Cont=234000±59319; OKT3+9.3 PT=209484±129630, Cont=234485±106213; OKT3+9.4 PT=463577±192609, Cont=446091±278407). The mRNA for IL-2 was found in all the patient groups as well as the controls. Conclusions: We conclude that children with SLE do not have defective lymphocyte proliferation with stimulation using OKT3 and anti-CD28 or anti-CD45. The mechanisms for T cell activation through the T cell receptor complex appear to be intact in children with SLE.

OKT3 prophylaxis in renal grafts with prolonged cold ischemia times: Association with improvement in long-term survival

The data on patients participating in two randomized, prospective studies with similar immunosuppressive regimens were updated and combined to evaluate the long-term effects of OKT3 according to cold ischemia time (< or = or > 24 hr). Among 159 patients in the OKT3 and 153 in the cyclosporine A (CsA) group, 8 and 12 deaths occurred, respectively (P = NS). In patients with cold ischemia > 24 hours, OKT3 prophylaxis resulted in a lower mean number of rejection episodes per patient than did CsA prophylaxis within one year (mean +/- SEM: 0.87 +/- 0.11 vs. 1.35 +/- 0.14, respectively; P = 0.008) and within five years (1.07 +/- 0.12 vs. 1.49 +/- 0.15, respectively; P = 0.032). In contrast, rejection incidences in patients with cold ischemia < or = 24 hours was not significantly different in the two groups. In all study patients, there was a trend towards higher graft survival rates in the OKT3 group versus the CsA group (at 5 years, 73% vs. 66%, respectively; P = 0.182). Among recipients of kidneys with cold ischemia times > 24 hours, OKT3 patients had significantly higher graft survival than CsA patients at two years (84% vs. 64%, respectively) and at five years (71% vs. 56%, respectively; P = 0.045). Significant differences were not observed in recipients of kidneys with cold ischemia times < or = 24 hours. In conclusion, patients receiving renal grafts with long cold ischemia times strongly benefit from OKT3 prophylaxis.

A RANDOMIZED PROSPECTIVE TRIAL OF PROPHYLACTIC IMMUNOSUPPRESSION WITH ATG-FRESENIUS VERSUS OKT3 AFTER RENAL TRANSPLANTATION

We carried out a randomized prospective trial to compare OKT3 (5 mg/d, 51 patients) with ATG-Fresenius (ATG-F, 4 mg/kg/d, 53 patients) for induction therapy after renal transplantation, concerning side effects, rejection, and infection incidence within a one year follow-up period. Concomitant immunosuppression included azathioprine/steroids from day 0 and cyclosporine A from day 4. OKT3 patients experienced significantly more and more-severe side effects, particularly pyrexia, headache, and pulmonary fluid overload. One-year graft survival was excellent in the ATG-F group (91%), but only 78% in the OKT3 group (P < 0.05) due to a series of rejections that occurred beyond day 100; patient survival (96% and 92%) was similar in both groups. OKT3-treated patients experienced more biopsy-proven rejections (0.6 +/- 0.1/pt.) than ATG-F patients (0.3 +/- 0.1, P < 0.05), and there was a similar, albeit not significant trend in clinical rejections (OKT3: 1.1 +/- 0.2/pt.; ATG-F: 0.8 +/- 0.1/pt.). Infections were more common in the OKT3 group (OKT3: 3.2 +/- 0.3, ATG-F: 2.0 +/- 0.2, P < 0.05), although this was entirely attributable to "minor" infections. On days 1 through 6, CD3 counts were more profoundly depressed with OKT3 therapy. Beyond day 10, however, CD3 counts were lower in the ATG-F group, as were CD2 counts, CD4 counts, and the CD4/CD8 ratio, suggesting a more prolonged immunosuppressive effect of ATG-F. Sensitization occurred more frequently with OKT3 (31%) than with ATG-F (10%), but was usually irrelevant, except in two patients (one in each group), whose grafts were lost because of immunization against OKT3 and ATG-F, respectively. In conclusion, a 7-day induction therapy with OKT3 does not improve outcome or diminish immunological graft loss when compared with ATG-F, but is associated with more rejections, infections, and side effects. ATG-F appears to be preferable for induction immunosuppression after renal transplantation.

Human mouse chimeric CD7 monoclonal antibody (SDZCHH380) for the prophylaxis of kidney transplant rejection.

mAb directed against CD7 have been shown to inhibit T cell proliferation in the allogeneic mixed lymphocyte reaction suggesting that CD7 may be an appropriate target for in vivo immunotherapy. We performed a prospective randomized clinical trial with a human-mouse chimeric CD7 mAb (SDZCHH380) and compared it with murine OKT3 for the prophylaxis of kidney transplant rejection. Twenty recipients of first cadaveric renal allografts were randomized to receive either SDZCHH380 or OKT3. SDZCHH380 was well tolerated. Rejection was delayed to day 35. No patients were sensitized to SDZCHH380. In contrast 7/10 OKT3 patients made anti-OKT3 antibodies. SDZCHH380 coated peripheral blood and lymph node T cells and, in contrast to OKT3, induced minimal release of IL-2, IL-6, TNF-alpha, and IFN-gamma. In addition, we showed that CD7-negative T cells mediated rejection in one of the SDZCHH380-treated patients. We conclude that the human-mouse chimeric CD7 mAb SDZCHH380 is well tolerated, is not immunogenic, and merits further study in the prophylaxis of transplant rejection.

A RANDOMIZED CLINICAL TRIAL OF INDUCTION THERAPY WITH OKT3 IN KIDNEY TRANSPLANTATION

A randomized, prospective multicenter trial was conducted to compare the safety and efficacy of OKT3 as an induction therapy with that of conventional immunosuppressive therapy administered to cadaveric renal allograft recipients. Two hundred fifteen patients were treated either with OKT3 plus azathioprine and steroids for 14 days with the delayed addition of cyclosporine on day 11, or with conventional immunosuppression (steroids, azathioprine, and cyclosporine). OKT3 patients had significantly fewer rejection episodes (51% vs. 66%, P = 0.032), a longer time to initial rejection (46 days vs. 8 days, P = 0.001), and fewer rejection episodes per patient (0.82 vs. 1.14, P = 0.014) than conventionally treated patients. Kaplan-Meier estimates of two-year graft and patient survival rates were 84% and 95%, respectively, for the OKT3-treated group, and 75% and 94%, respectively, for the conventionally treated group. Following a subsequent first rejection episode, OKT3 reversed 93% of the rejections in patients receiving OKT3 induction therapy and 94% in patients receiving conventional therapy. Adverse experiences reported during OKT3 induction therapy were similar to those seen when the drug was used for rejection. Following initial exposure, 40.3% of the patients tested were positive for anti-OKT3 antibody, only 6.7% of which were of high titer (1:1000). In the presence of low titer (1:100 or less) antibody, OKT3 was successful in reversing rejection in five of six retreated patients tested. In conclusion, treatment with OKT3 (in combination with azathioprine, steroids, and the delayed addition of cyclosporine) is an effective approach for renal allograft maintenance.

THE LONG-TERM OUTCOME OF OKT3 COMPARED WITH CYCLOSPORINE PROPHYLAXIS AFTER LIVER TRANSPLANTATION

We report the long-term follow-up (greater than 1 year) of 46 patients (12 pediatric) randomized to receive OKT3 for the first 14 days after OLT with low-dose steroids compared with 39 patients (8 pediatric) who received cyclosporine, steroids, and azathioprine. The mean period of follow-up for survivors was 648 +/- 261 days for the OKT3 group and 682 +/- 216 days for the cyclosporine group. Of the OKT3 patients, 46% were rejection-free in the first month compared with 31% of CsA-treated patients (P = NS). Rejection occurred after 1 month in 21% of the OKT3 group patients compared with 19% of the CsA group patients. One patient in each group developed vanishing bile duct syndrome. Eight patients in the OKT3 group and 13 in the CsA group experienced steroid-resistant rejection and required OKT3 rescue. In the 8 patients in whom OKT3 was reused, 4 had a positive ELISA after prophylaxis, and in 6, CD3-positive cells were greater than 10% during OKT3 reuse. Five patients resolved the episode. Of patients receiving OKT3 prophylaxis, 39% developed anti-OKT3 antibodies. In the OKT3 group 83% of patients and in the CsA group 75% currently have normal liver function. There was no difference in serum creatinine for either adult or pediatric recipients at 12 months in the two groups. Eight episodes (2 CMV) of severe infection occurred after 1 month in the OKT3 group compared to 11 (4 CMV) in the CsA group. Graft survival, 63% for the OKT3 group and 73% for the CsA group, and patient survival, 67% for the OKT3 group and 84% for the CsA group, were not significantly different in the two groups. We recommend reserving the use of OKT3 for resistant rejection or when cyclosporine is contraindicated, as we can show no long-term benefit from its routine prophylactic use.

A RANDOMIZED PROSPECTIVE COMPARISON OF MALG WITH OKT3 FOR RESCUE THERAPY OF ACUTE MYOCARDIAL REJECTION

A randomized prospective trial for rescue therapy from acute myocardial rejection was undertaken utilizing Minnesota antilymphoblastic globulin (n = 15) versus murine monoclonal anti-CD3 antibody therapy (OKT3) (n = 14). Patients included in the study had moderate rejection unresponsive to bolus high-dose steroid therapy, or moderate-to-severe rejection with hemodynamic instability. Analysis was performed using the t test and chi-square, significance was P less than 0.05. Patient age, sex, interval from transplant to treatment, and number of unresponsive patients vs. hemodynamically unstable patients were similar in both groups (P greater than 0.05). Initial resolution occurred in 9/15 MALG- vs. 14/14 OKT3-treated patients (P = 0.017). Secondary resolution following repeat treatment occurred in 5/6 remaining MALG patients, for a final resolution of 14/15 MALG vs. 14/14 OKT3 patients (P = NS). Rebound rejection was not significantly different (1/14 MALG vs. 4/13 OKT3). However, 7/14 OKT3-treated patients developed life-threatening infections (1 CMV pancreatitis, 2 CMV pneumonias, 1 systemic candidiasis, 3 CMV viremia) vs. 1/15 MALG-treated patients (CMV viremia) (P = 0.014). Death occurred in 4/14 OKT3- (infection) vs. 1/14 MALG- (rejection) treated patients (P = NS). There were no significant differences in the rate of resolution, rebound, infection, or outcome between unresponsive or hemodynamically unstable patients within either group. Although initial rescue is significantly better with OKT3, final resolution is the same in both groups. Since there was a significant incidence of life-threatening infections (7/14) leading to 4 deaths with OKT3 treatment, we recommend MALG for rescue therapy of refractory acute myocardial rejection if this immunosuppressive regimen is to be used.

OPTIMAL PERIOPERATIVE IMMUNOSUPPRESSION IN CARDIAC TRANSPLANTATION USING RABBIT ANTITHYMOCYTE GLOBULIN

A randomized trial of RATG (polyclonal) vs. OKT3 (monoclonal) antibody prophylaxis was carried out in 82 cardiac transplant recipients who, in addition, received baseline immunosuppression with cyclosporine, azathioprine and prednisone. One-year actuarial survival was comparable between groups (95% and 98%). The incidence of moderate or severe rejection within the first 30 days of transplant was over 7 times greater in patients receiving OKT3 vs. those receiving RATG. Patients receiving OKT3 were more likely to have repeated episodes of rejection and the mean time to rejection for patients receiving OKT3 was shorter (33 days) than for RATG patients (67 days). At 120 days, 52% of RATG patients were free of rejection while only 37% of the OKT3 patients were rejection-free. There was no difference in the incidence of major or minor bacterial or viral infection between groups. Patients receiving OKT3 showed a less-prolonged depression of the CD3 and CD4 T cell subsets than did those receiving RATG. Significant hemodynamic side-effects were seen after the first dose of OKT3 and there was a 5% incidence of aseptic meningitis associated with its use.

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.