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.
Suthanthiran
M
M
Department of Medicine, Cornell University Medical College, New York, NY.
Fotino
M
M
Riggio
R R
RR
Cheigh
J S
JS
Stenzel
K H
KH
D000911:Antibodies, Monoclonal / Q000009:adverse effects*; D015703:Antigens, CD / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D016853:Muromonab-CD3; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D016853:Muromonab-CD3; D007371:Interferon-gamma