OKT3 Research Articles

Muromonab CD-3: a review of its pharmacology, pharmacokinetics, and clinical use in transplantation.

Muromonab CD-3 (OKT-3) is a monoclonal antibody that is highly effective in the treatment of acute rejection in solid organ transplants. Due to its monoclonal nature, each molecule is identical because it is derived from a single antibody-producing clone. OKT-3 is administered only by intravenous injection and has a harmonic half-life of approximately 18 hours. It binds specifically to the CD-3 complex, which is involved in antigen recognition and cell stimulation, on the surface of T lymphocytes. Immediately after administration CD-3-positive T lymphocytes are abruptly removed from the circulation. The route of metabolism for OKT-3 is not clear; it may be removed by opsonization by the reticuloendothelial system when bound to T lymphocytes, or by human antimurine antibody production. The agent has been effective in reversing corticosteroid-resistant acute rejection in renal, liver, and cardiac transplant recipients. Its use in pancreatic and bone marrow recipients is inconclusive. OKT-3 has a considerable number of initial side effects, and some life-threatening reactions may occur. This drug should not be administered to any patient who is greater than 3% usual body weight because of the potential for the development of severe pulmonary edema. OKT-3 may also be associated with a high rate of infection, especially of the viral type. The usual dose is 5 mg administered as an intravenous bolus over 2-4 minutes daily for 10-14 days. Approximately 85% of patients treated with OKT-3 develop reactive human antimurine antibodies that, over time, may lead to tachyphylaxis and neutralization of the murine antibody OKT-3. OKT-3 is potent immunosuppressive agent and is an important prototype of future monoclonal antibodies.

OKT 3

OKT 3

ABO-Incompatible Kidney Transplantation with Donor-Specific Skin Graft

From November 3, 1975, to May 31, 1989, 711 (548 living-related and 163 cadavers) kidney transplantations were performed in our centers. In the final 2 years, 15 ABO-incompatible living related kidney transplantations were performed. In 4 cases, the recipient's blood groups was O and the donor's A1. In 3 cases the blood group of the recipient was A1 and the donor's AB, two patients were B with the donors A1 and the other 2 were O with donors B. The other 3 recipients group was B and the donors' were AB. The donors' and recipients' HLA-AB typing showed one haplotype matching in 12 and two haplotypes matching in 3 patients. The donors were mothers in 7 cases, sibling in 5, and father in 3 cases. At least 3 weeks before the renal transplantation, donor-specific skin grafts and subsequently splenectomy were performed on 9 recipients, but on 6 recipients without splenectomy. Following the skin graft, cross-match was done starting from the 15th day and then continued every week. The immunosuppression, which consisted of triple drugs (0.5 mg/kg prednisolone, 2 mg/kg cyclosporin-A and 2 mg/kg azathioprine) was followed by skin graft. Renal transplantation was performed according to cross-match and skin graft results, and all recipients prior to surgery received at least two sessions of plasmapheresis. Regular dose of immunosuppression that included triple drugs were used after the kidney transplantation and then Orthoclone OKT-3 and plasmapheresis were applied during the rejection episodes without bolus therapy. All patients were followed for 5 to 24 months (ave. 14,13 months).(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular Collapse Following Orthoclone OKT3 Administration: A Case Report

Orthoclone OKT3 has been described to have significant adverse effects on the cardiovascular system, including pulmonary edema, angina, dysrhythmias, hypertension, and hypotension, usually following the first or second doses of the drug. We describe a case of cardiopulmonary arrest in a patient 1 minute after the initial injection of OKT3. Two subsequent doses were successfully administered with the guidance of hemodynamic monitoring, which showed profound, immediate effects of OKT3 on the cardiovascular system. Potential mechanisms of these effects are discussed.

Haemodynamic evaluation in cardiac transplant recipients during use of orthoclone OKT3 monoclonal antibody for rejection prophylaxis

Haemodynamic evaluation in cardiac transplant recipients during use of orthoclone OKT3 monoclonal antibody for rejection prophylaxis

Principles of Immunosuppression

One-year graft survival rates of 80% to 90% can now be achieved routinely for primary cadaveric transplants with a variety of CSA-containing regimens. Further improvement of these excellent results may be difficult because large numbers of patients must be evaluated to provide meaningful conclusions. On the other hand, long-term follow-up of CSA-treated patients has revealed a trend of undaunted allograft attrition with time. Future efforts therefore should be directed at improving long-term allograft results at 5 to 10 years. Further improvement of transplant outcome may be sought through better use of the currently available immunosuppressants or from newer agents. The long-term impact of CSA administration requires further evaluation. Although potent combination protocols provide effective protection against rejection, the potential development of neoplasms must be studied in long-term follow-up. On the other hand, unwarranted fear of progressive nephrotoxicity may result in underdosing of CSA and a high incidence of late rejections. The advent of mAbs has spawned an exciting era of specific immunosuppression. These newer agents may eventually help curtail the complications associated with the current regimens.

OKT 3

OKT 3

Neurotoxicity after Treatment with Muromonab-CD3

Neurotoxicity after Treatment with Muromonab-CD3

OKT 3

OKT 3

Failure of orthoclone okt3 retreatment in a pancreas transplant recipient with antimurine antibodies

Orthoclone OKT3 is a murine monoclonal antibody that blocks the generation and function of T lymphocytes. It has been shown to be effective in reversing acute cellular rejection in solid organ transplants. However, potential development of antimurine antibodies restricts the duration that the drug can be used and the ability to reuse the drug. The case reported in this article illustrates the failure of retreatment with OKT3 when high titer (1:3200) antimurine antibodies are present. Lack of efficacy of the drug was documented by virtually undetectable circulating OKT3 levels in plasma, no decrease in T3 lymphocytes, and organ rejection. OKT3 should only be reused when immune monitoring (antimurine antibody status, lymphocyte subsets, and OKT3 plasma levels) is performed before, during, and after its use. Patients with high-titer anti-OKT3 antibody should not be retreated with OKT3.

Adverse Responses Following Intraoperative Administration of Orthoclone OKT3

Adverse Responses Following Intraoperative Administration of Orthoclone OKT3

OKT 3

OKT 3

Critical Care Supplement: Reversing Cardiac Transplant Rejection with Orthoclone OKT3

Critical Care Supplement: Reversing Cardiac Transplant Rejection with Orthoclone OKT3

A flow cytometric method for the detection of the development of antibody to Orthoclone OKT3

Orthoclone OKT3 is a monoclonal antibody used in the treatment of transplant rejection. The development of anti-OKT3 antibodies after therapy with this drug is a side effect which must be monitored. The current ELISA test to detect these antibodies is difficult to standardize between laboratories and does not lend itself to frequent monitoring of small numbers of samples. This prompted us to develop a new method employing flow cytometry to detect the development of anti-murine antibodies. Comparing samples tested by both techniques, we found the flow cytometric method to be more sensitive and as specific as the ELISA methodology. This technique is adaptable to numerous serologic assays and could greatly expand the use of flow cytometry in the clinical laboratory.

Muromonab CD3

Muromonab CD3 (Orthoclone OKT3, Orthoclone, OKT3) is the first monoclonal antibody to become available for therapy in humans. In effect it blocks all cytotoxic T cell function. Clinical trials show that muromonab CD3 is effective in reversing acute renal, hepatic, cardiac and combined kidney-pancreas transplant rejection episodes. It has also been shown to be effective in the treatment of rejections resistant to conventional treatment. As such it offers a significant alternative when no other therapeutic option remains open. Other clinical trials have shown that muromonab CD3 is more effective than high-dose corticosteroids in reversing first episodes of acute renal and hepatic rejection. Additionally, it appears effective as a prophylactic treatment against acute renal and cardiac rejection in the immediate post-transplantation period. Preliminary studies also indicate that it may be effective in preventing or reversing graft-versus-host disease in bone marrow transplant patients. The development of neutralising antibodies may limit the effectiveness of a second course of muromonab CD3 therapy in some patients. In conclusion, muromonab CD3 offers a significant new approach to immunosuppressive therapy and has provided a valuable therapeutic alternative for the treatment of acute solid organ transplant rejection.

Remission of psoriatic lesions with muromonab-CD3 (Orthoclone OKT3) treatment

A 39-year-old woman received a 10-day treatment with muromonab-CD3 (Orthoclone OKT3) (total dose 50 mg) as part of a clinical trial designed to test its efficacy in the treatment of multiple sclerosis. The patient concomitantly received methylprednisolone (Solu-Medrol), 50 mg on the first day of treatment, and indomethacin, 50 mg, three times daily throughout the 10-day course. She had had psoriasis vulgaris for 18 years, which was largely confined to extensor surfaces of her arms and legs. She had received intermittent treatment with topical coal tar preparations in the past without benefit. The condition

Aseptic meningitis associated with muromonab CD3 administration

Aseptic meningitis associated with muromonab CD3 administration

OKT3 SALVAGE THERAPY IN A QUADRUPLE IMMUNO SUPPRESSIVE 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.

Glomerular T cell and monocyte populations in patients with IgA nephropathy.

Renal tissues from 19 patients with the minimal or slight stage of IgA nephropathy were examined for evidence of glomerular T cell or monocyte infiltration using monoclonal antibodies to identify T cells (OKT3, OKT11), T cell subsets (OKT4, OKT8), and monocytes and null cells (OKM1) by indirect immunofluorescence. Renal tissues from 12 patients at the same stage of mesangial proliferative glomerulonephritis without IgA deposition were also investigated by these procedures. Light microscopic examination of the same renal tissues was also performed. Reactive glomerular mononuclear cells were found to be numerous in patients with IgA nephropathy. The most prominent type of glomerular cells was OKT8 positive. T cell subsets and OKM1 positive cells in glomeruli from patients with IgA nephropathy were significantly increased as compared to those from patients with mesangial proliferative glomerulonephritis. Focal segmental proliferation of mesangial cells was observed in glomeruli which showed an accumulation of OKT8 positive cells. It is concluded that the immuno-regulatory mechanism involving T cells and/or monocytes might be one of the exacerbating factors in patients with IgA nephropathy.

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.