Mechanisms of immunosuppression induced by antithymocyte globulins and OKT3

Abstract

OKT3 monoclonal antibody and polyclonal antithymocyte or antilymphocyte globulins are among the most potent immunosuppressive agents which have been used in organ transplantation for many years. Both induce a rapid and profound lymphocytopenia classically attributed to several mechanisms, such as complement-dependent cytolysis, cell-mediated antibody-dependent cytolysis, as well as opsonization and subsequent phagocytosis by macrophages. However, the relative contribution of these three Fc-dependent mechanisms in vivo is difficult to ascertain and may be less important than previously thought. In addition OKT3 induces T-cell receptor modulation in vivo and modulated T cells no longer interact with antigen-presenting cells. Modulation of the T-cell receptor complex has not been documented for antithymocyte and antilymphocyte globulins 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 directed against CD3 and other functional molecules on the surface of T and B cells, generate various transduction signals to the target cells which can affect their functions in different ways. Recent in vitro studies suggest that these antibodies interfere with activation signals. Indeed, antithymocyte and antilymphocyte globulins, at low concentrations, inhibit T-cell activation induced by alloantigens, whereas they induce polyclonal T-cell activation at higher concentrations. Mitogenic 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 hypothesize from in vitro data that in spite of their nonspecific immunosuppressive effects which may result in severe iatrogenic immunodeficiency, antilymphocyte antibodies may also act on stimulated alloreactive T-cell clones and therefore contribute to donor-specific graft adaptation.