MECHANISMS OF ACTION OF INTRAVENOUS IMMUNE GLOBULIN IN IMMUNE-MEDIATED DISEASES

Intravenous immune globulin (IVIG) exhibits a number of immunomodulato ry properties that are mediated by the Fc portion of IgG and by the sp ectrum of variable (V) regions contained in the immune globulin prepar ations. Five predominant and non-exclusive mechanisms of action have b een proposed to account for the immunomodulatory effects of IVIG in im mune-mediated diseases: (i) functional blockade of Fc receptors on spl enic macrophages; (ii) inhibition of complement-mediated damage, an ef fect that is dependent on the ability of IgG to bind C3b and C4b and t hus reduce the number of activated complement fragments that may depos it on target surfaces of complement activation; (iii) modulation of th e production of cytokines and cytokine antagonists; (iv) neutralizatio n of circulating autoantibodies by complementary (e.g. anti-idiotypic) antibodies in IVIG, a mechanism that accounts for the rapid decrease in titre of circulating autoantibodies that is often observed within h ours following the infusion of IVIG; (v) selection of immune repertoir es, a complex set of effects that may be observed in individuals recei ving IVIG far beyond the half-life of the infused immunoglobulin and t hat is directly relevant to the ability of IVIG to, for example, suppr ess autoantibody-producing clones in patients with antibody-mediated a utoimmune disease and modulate graft versus host disease (GVHD). IVIG has been shown to downregulate or activate B-cell clones expressing su rface IgG that is complementary (anti-idiotypic) to V regions of antib odies present in IVIG. IVIG has been shown also to interact with surfa ce molecules of T cells that are essential to immune regulation, such as the ap TCR, CD5, CD4, non-polymorphic determinants of MHC class I m olecules and adhesion molecules of T and B cells. The complex interact ions of IVIG with functional molecules of cells of the immune system a re relevant to its therapeutic effects in T cell- as well as B cell-me diated diseases and indeed, to our understanding of the physiological role of normal IgG and antibody networks in controlling autoreactivity in healthy individuals.