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. |
