Effect of immunosuppressants on OKT3 associated T cell activation: clinical implications.
The monoclonal antibody directed at the T cell differentiation antigen T3 (CD3, T.gp 20-25) appears to be superior to conventional high-dose steroids in the treatment of rejection in cadaveric renal graft recipients. Re-rejection episodes and other adverse reactions, probably secondary to T cell activating potential of anti-T3, continue to be clinical problems with anti-T3 therapy. We therefore examined the relative efficacy of cyclosporin A (CSA), methylprednisolone (MP), or 6-mercaptopurine (6-MP), at concentrations that are readily accomplished in clinical practice, on the activation of T cells by anti-T3. CSA or MP mediated marked and 6-MP mediated modest inhibition of anti-T3 induced proliferation of alloimmune memory T cells. CSA- or MP-inhibited anti-T3 elicited specific secondary cytolytic activity and natural killer (NK) cell activity, and 6-MP failed to prevent the augmentation of NK cell activity mediated by anti-T3. The immunosuppressants also exhibited differential effects on anti-T3-associated lymphokine production by peripheral blood mononuclear cells. Interleukin 2 production was completely inhibited by CSA, modestly inhibited by MP and not inhibited by 6-MP. Interferon gamma production was completely inhibited by CSA or MP and not inhibited by 6-MP. Our findings, in addition to providing a plausible immunological basis for some of the complications of anti-T3 therapy, provide experimental support for therapeutic strategies that include the use of CSA and/or MP along with anti-T3.
D000911:Antibodies, Monoclonal / Q000276:immunology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D003524:Cyclosporins / Q000494:pharmacology; D006801:Humans; D007156:Immunologic Memory; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects*; D015122:Mercaptopurine / Q000494:pharmacology; D008775:Methylprednisolone / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D003524:Cyclosporins; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D007371:Interferon-gamma; D015122:Mercaptopurine; D008775:Methylprednisolone