OKT3-associated adverse reactions: Mechanistic basis and therapeutic options
OKT3, a prototypic monoclonal antibody directed at the lineage-specific CD3 antigen expressed on mature T cells, is an effective immunosuppressant in organ graft recipients. Unfortunately, a variety of adverse reactions are observed following the first and second doses of OKT3. In a series of experiments designed to examine the signaling repertoire of OKT3, it was found that (1) OKT3 is an effective substitute for the alloantigen stimulus in the activation of antigen-specific memory T cells; (2) OKT3 is a potent inducer of cytolytic activity (secondary cytotoxic T-cell activity as well as natural killer-cell activity); (3) OKT3 is also an inducer of interleukin-2 and interferon gamma production; and (4) of the immunosuppressants currently in clinical use, cyclosporine greater than methylprednisolone greater than 6-mercaptopurine (an in vivo cleavage product of azathioprine) in curtailing T-cell activation with OKT3. Collectively, these observations suggest a potential mechanistic basis for the adverse reactions associated with OKT3 and provide experimental support for therapeutic strategies that include the use of cyclosporine and/or methylprednisolone before OKT3 administration.