Several mechanisms contribute to the immunoregulatory effects of intravenous immunoglobulin (IVIg) in immune-mediated diseases, either by interfering with the selection and expansion of specific (e.g. autoreactive) lymphocyte clones or by inhibiting peripheral effector mechanisms of disease. Some of the effects of IVIg are mediated by the interaction of the Fc portion of IgG with plasma proteins or specific cellular receptors; other effects are primarily dependent on the broad spectrum of variable (V) region reactivities expressed in the IVIg pool. Proposed mechanisms of action of IVIg include: (1) the functional blockade of Fc receptors on splenic macrophages, an effect that likely accounts for the increase in platelet numbers in patients with ITP; (2) several distinct mechanisms, including the inhibition of complement activation and modulation of the production of monocytic cytokines, that result in profound anti-inflammatory effects of IVIg. By binding C3b and C4b, IVIg reduces the amount of activated complement fragments deposited on target surfaces of complement activation, which has been shown to be of relevance in patients with dermatomyositis treated with IVIg; IVIg was also shown to selectively induce the monocytic cytokine antagonist IL-..., which accounts for the rapid decrease in serum levels of markers of inflammation that is observed within hours of administration of IVIg. In several systemic inflammatory diseases, the anti-inflammatory properties of IVIg have allowed for a decrease in the daily requirements for corticosteroids; (3) the neutralization of circulating antigens and superantigens by specific antibodies in IVIg and the V region-dependent neutralization of circulating autoantibodies by complementary anti-V region (anti-idiotypic) antibodies present in the IVIg pool. The latter mechanism accounts for the early decrease in the titer of circulating autoantibodies often observed in patients with autoantibody - associated autoimmune diseases following infusion of IVIg; (5) a complex set of mechanisms resulting in the selection of expressed B and T cell immune repertoires. These effects are directly relevant to the ability of IVIg to down-regulate autoantibody-producing clones in patients with autoimmune disease. In autoimmune patients, IVIg was shown to selectively down-regulate or activate B cell clones expressing surface Ig that is idiotypically complementary to antibodies present in IVIg; it restores patterns of spontaneous fluctuations of autoantibodies in the serum of treated patients similar to those observed in healthy individuals. In experimental models, IVIg (or normal homologous immunoglobulin) was shown to interfere with the maturation and migration to the periphery of immature B cells; to induce specific T cell unresponsiveness to the immunizing autoantigen; to modulate cytokine production by T cells, shifting toward a «normal equilibrium» enhanced Th1 or Th2 responses that predominate at the induction phase of certain diseases. All these effects are for an important part, mediated by the presence in IVIg of natural IgG autoantibodies against surface molecules of antigen-presenting cells, B and T lymphocytes that are critical for the regulation of the immune response and induction of tolerance. Thus, IVIg contains antibodies to the αβ TCR, to CD5, CD4, to non-polymorphic determinants of MHC class I molecules and to ligands of integrins, that inhibit the biological effects dependent on the interaction of these antibodies with their respective ligands.

The understanding of the complex molecular and cellular mechanisms involved in the immunoregulatory effects of IVIg should provide a basis for «second generation» therapeutic preparations of normal immunoglobulin with increased efficacy for the treatment of immune-mediated diseases.