Guidelines for the Optimal Use of Muromonab CD3 in Transplantation

Abstract

Muromonab CD3 (OKT3), the murine anti-CD3 monoclonal antibody (mAb) of the IgG-2a class, directed against the CD3 molecule on the surface of human T cells, has proven to be a powerful immunosuppressive agent in solid organ transplantation and has been shown to be superior to high-dose steroids as first-line treatment of acute allograft rejection. It is comparable to antithymocyte globulin (ATG) in treating steroid-resistant rejection and it is also effective as rescue treatment in ATG-resistant rejection. However, OKT3 treatment is followed by a substantial percentage of re-rejections, most of which respond well to steroids. In the early post-transplant period, a prophylactic course of OKT3 can delay the onset of acute rejection, in particular in immunologically high-risk patients. First-dose-related adverse effects (pyrexia, dyspnoea, headache, nausea, vomiting and diarrhoea) of OKT3 are severe, but usually transient and seldom life-threatening, provided overhydration has been corrected and steroids have been given before the first administration. These adverse effects are partly attributed to the release of cytokines as a result of mononuclear cell activation. In addition, complement activation and subsequent activation of neutrophils may play a role in their pathogenesis. After exposure of patients to OKT3 an increased incidence of infections and malignancies has been reported. However, most likely this merely reflects the total burden of immunosuppression. Xenosensitisation represents an important limitation to OKT3 treatment, although a second or third course can still be effective in patients with low antibody titres. In practice, the initiation of OKT3 treatment should be preceded by correction of overhydration, if necessary by means of dialysis or ultrafiltration. According to the instructions from the manufacturer the first dose of OKT3 is preceded by paracetamol (acetaminophen), an antihistamine and intravenous (IV) corticosteroids, in an attempt to mitigate the first dose-related symptoms. A regimen consisting of administration of 2 IV doses of 250mg methylprednisolone, given 6 hours and 1 hour before the first OKT3 injection, followed by a 2-hour infusion of OKT3, is most effective in diminishing OKT3-induced adverse effects.