At the present time, we assume that all effects of IVIG are related to the quantity and quality of IgG in the product. Various mechanisms may be important in the different therapeutic uses of IVIG, including (1) replacement therapy for primary and secondary immunodeficiencies, (2) specific passive immunotherapy, and (3) management of specific inflammatory and/or immunologic disorders.
Efficacy of IVIG infusions in primary immunodeficiency diseases is probably related to replacement of antibodies to environmental pathogens. Despite variations in the titer of specific antibodies, all licensed preparations are apparently efficacious in the treatment of these diseases. In addition, pooled antibodies may have physiologic activities other than pathogen recognition that may contribute to the beneficial effects of replacement therapy.
The effectiveness and the mechanism of action of IVIG in secondary immunodeficiencies such as indolent lymphomas is presumed to be similar to that in primary immunodeficiencies. In these diseases, a reasonable correlation between rates of systemic infection and concentrations of serum immunoglobulins supports this presumption. The benefit of prophylactic replacement of IgG in very low birth weight infants is not established. Attempts to replace antibodies may be rational in this situation. However, it is possible that administration of immunoglobulin from large donor pools could adversely affect the development of the infant's immune system, as there is substantial evidence in mice that anti-idiotypic antibodies may profoundly affect immune responsiveness. For conditions such as bone marrow transplantation and pediatric HIV infection, the complexity of immunologic abnormalities will make determination of mechanisms extremely difficult. IVIG is also being used for specific passive immunotherapy. In these instances, the titers of specific antibodies are of paramount importance. Moreover, consideration must be given to the possibility that large amounts of apparently irrelevant antibodies may block receptors on the surface of phagocytes and thus interfere with effective disposal of microbial pathogens.
In the treatment of ITP, there may be multiple mechanisms of IVIG action. The platelet count increase occurring within several days of the initiation of therapy appears to be caused by diminished sequestration of autoantibody-sensitized platelets. This may be caused by interference with Fc receptors on the cells of the monocyte-macrophage system. A similar mechanism may operate in other autoimmune and alloimmune cytopenias. Sustained responses to IVIG may represent spontaneous remissions or may be related to an immunosuppressive effect of IVIG.
There are several possible mechanisms by which the infusion of large concentrations of immunoglobulins may have an immunosuppressive effect. The presence of IgG dimers in immunoglobulin preparations, a result of pooling samples from a large number of individual donors, likely represents the occurrence of idiotype-anti-idiotype complexes. There is evidence that anti-idiotype antibodies in IVIG react with epitopes on the autoantibodies in patients with thyroiditis or spontaneous factor VIII inhibitors. Alterations of T-cell subsets and of in vitro B cell function, both spontaneous and mitogen driven, have been reported in patients treated with IVIG. It is unknown if these observations are related to a mechanism of therapeutic effect.
A striking anti-inflammatory effect of IVIG has been observed. This phenomenon is most apparent in Kawasaki syndrome, where reductions in fever, neutrophil counts, and acute phase reactants regularly occur within a day or so of initiation of treatment. This effect is not unique to Kawasaki syndrome but has been seen in other inflammatory disorders. The mechanisms are unknown but may be distinct from those that mediate immunosuppression. One possible mechanism demonstrated in experimental animals is the inhibition of complement-dependent tissue damage caused by binding of IVIG to active C3 fragments.
There is a great need for an understanding of the mechanisms of IVIG in the various conditions in which it is used. A variety of mechanisms have been suggested but none proven. Mechanistic hypotheses such as the provision of anti-idiotype antibodies, Fc receptor blockade, and alteration of reticuloendothelial cell system function should be rigorously tested. Utilization of appropriate animal models would provide an efficient way to test these hypotheses.