MECHANISMS OF IMMUNOSUPPRESSION INDUCED BY ANTITHYMOCYTE GLOBULINS AND OKT3

OKT3 monoclonal antibody and polyclonal antithymocyte or antilymphocyt e globulins are among the most potent immunosuppressive agents which h ave been used in organ transplantation for many years. Both induce a r apid and profound lymphocytopenia classically attributed to several me chanisms, such as complement-dependent cytolysis, cell-mediated antibo dy-dependent cytolysis, as well as opsonization and subsequent phagocy tosis by macrophages. However, the relative contribution of these thre e Fc-dependent mechanisms in vivo is difficult to ascertain and may be less important than previously thought. In addition OKT3 induces T-ce ll receptor modulation in vivo and modulated T cells no longer interac t with antigen-presenting cells. Modulation of the T-cell receptor com plex has not been documented for antithymocyte and antilymphocyte glob ulins as yet. The monoclonal antibody OKT3, which is directed against the epsilon chain of the CD3 molecule on the T-cell surface, but also antithymocyte and antilymphocyte globulins, which contain antibodies d irected against CD3 and other functional molecules on the surface of T and B cells, generate various transduction signals to the target cell s which can affect their functions in different ways. Recent in vitro studies suggest that these antibodies interfere with activation signal s. Indeed, antithymocyte and antilymphocyte globulins, at low concentr ations, inhibit T-cell activation induced by alloantigens, whereas the y induce polyclonal T-cell activation at higher concentrations. Mitoge nic antibodies can trigger an activation-induced cell death phenomenon as documented with anti-CD3 antibodies. Anti-CD3 antibodies can also induce a state of specific unresponsiveness (clonal anergy) which may contribute to their long-lasting immunosuppressive effect. One may hyp othesize from in vitro data that in spite of their nonspecific immunos uppressive effects which may result in severe iatrogenic immunodeficie ncy, antilymphocyte antibodies may also act on stimulated alloreactive T-cell clones and therefore contribute to donor-specific graft adapta tion.