IgG was one of the first plasma proteins prepared in a purified state as a therapeutic drug for treatment of clinical disorders. It remains, along with albumin and α -proteinase inhibitor, the most widely used therapeutic plasma derivative and is currently the major plasma product on the global market. Polyvalent human immunoglobulin preparations have been used to reconstitute humoral immunity in agammaglobulinemic patients for more than three decades. Until 30 years ago, intramuscular treatment was the mode of administration. Intramuscular preparations caused severe adverse reactions when injected intravenously. The most serious were anaphylactoid reactions and were probably complement mediated. Efforts to reduce anticomplementary activity and the prekallikrein activator activity were initiated in the early 1980s and safer IVIg preparations became available.

IVIg is prepared from pooled human plasma pools of 3000 to 50,000 L. The World Health Organization requires more than 1000 donors per lot. The majority of IVIg is produced by cold ethanol fractionation procedures, with filtration and polishing chromatography steps added to increase yield and decrease pathogen transmission. Gamunex (Talecris Biotherapeutics) is produced from cold ethanol fractionation followed by caprylate precipitation and chromatograpy. This is the first significant change in commercial IVIg production in 20 years. IVIg contains concentrated IgG with normal plasma ratios of IgG1 and IgG2, lower percentages of IgG3 and IgG4, and only trace amounts of IgA and IgM. It retains the antibody repertoire, reflecting the combined immunologic experience of the donors. Hyperimmune IVIg is purified from donor plasma selected for high titer toward a specific pathogen. Prophylaxis for cytomegalovirus and respiratory syncytial virus are two approved clinical applications.

The availability of safe IVIg preparations and the fortuitous observation that IgG treatment of a patient with thrombocytopenia and IgG deficiency increased the patient’s platelet count began an intense period of clinical use of IVIg for indications other than primary immune deficiency. In 1990, the National Institutes of Health sponsored a Consensus Development Conference, which produced the first consensus statement on IVIg clinical indications. As a result, six dis ease indications—primary immunodeficiency, Kawasaki syndrome, chronic lymphocytic leukemia, human immunodeficiency virus (HIV) infections during childhood to prevent infections, BM transplantation to prevent graft-versus-host disease or bacterial infections in adults, and idiopathic purpura—were approved by the US Food and Drug Administration (FDA) for labeling and marketing. The licensed indications remain unchanged, but off-label uses include more than 100 conditions. Recently, hyaluronidase has been used to facilitate subcutaneous administration of immune globulin preparation, and this has now become an option for the treatment of patients with immune deficiency. These preparations can be self-administered and may result in fewer reactions. However, they need to be given more frequently, there are subcutaneous reactions, they are not licensed for the treatment of hematologic conditions, and it is recommended they not be used for ITP.

The experience with IVIg clinical development has been largely empiric and anecdotal. The mechanisms for patient benefit or harm are poorly understood, especially for high-dose immune modulation therapy. Various known and some yet undiscovered functions of immunoglobulins in immune homeostasis may contribute, including modulation of the function and expression of Fc receptors, interaction with complement and cytokine systems, antiidiotypic antibodies, and regulation of T-cell and B-cell function.

Many effects of IVIg are explained by mechanisms beyond anti genic recognition of pathogens. IVIg preparations contain up to 30% dimers composed of idiotype–antiidiotype antibody pairs. These dimers appear to be very effective as a sink for activated complement and can inhibit complement activation.  Benefit for treatment of immune thrombocytopenia purpura seems to be mediated by Fc-receptor blockade of the reticuloendothelial cell salvage receptor, also known as FcRn. Therefore, if the FcRn is saturated with infused immunoglobulin, this may decrease the half-life of any autoantibodies that are being produced. This, together with an antiidiotypic neutralization of antiplatelet antibody will eliminate antiplatelet anti bodies from the plasma. Similarly, these mechanisms may explain the rapid therapeutic effect of IVIg in patients with acquired inhibitors to factor VIII.  Other indications of antibody neutralization can be seen in IVIg treatment of myasthenia gravis. The dramatic success of IVIg in treating Kawasaki syndrome may be attributable to several mechanisms, including antiidiotypic neutralization of antiendothelial antibodies, inhibition of cytokine production and function, and elimination of causative superantigens. IVIg inhibits B-cell activation and autoantibody production by enhancing CD8 + sup pressor T-cell function. Cell-mediated immunity is also affected. As mentioned earlier, Kaneko et al.  ascribe much of the effect of IVIg to a small fraction of it that is sialylated. A 2011 report from this group suggests a mechanism for the way that sialylated IgG in IVIg downmodulates the inflammatory response of the immune system.  They suggest that the sialylated IgG Fc region binds to DC-SIGN, a molecule on the surface of “regulatory” myeloid cells, including DCs. In response to DC-SIGN ligation by sialylated IgG, these cells secrete the cytokine IL-33, which in turn stimulates IL-4 production by basophils. IL-4 upregulates the synthesis of the “inhibitory” class of Fc γ R on effector macrophages, namely Fc γ RIIB. Because ligation of this class of Fc γ R by immune complexes actually results in the recruitment of regulatory phosphatases, which shut down intracellular signaling cascades, the net effect is to increase the activation threshold required to initiate inflammation by these effector cells.

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مواضيع ذات صلة

Therapeutic Passive Immunization and Monoclonal Antibody Therapy

Adverse Events Related to Intravenous Immunoglobulin Infusion

Immunoglobulins

Complement and Cancer

Complement and T-Cell Immunity

Focusing Antigen on Follicular Dendritic Cells

B-Lymphocyte Coreceptors

The Complement System : Alternative Pathway

The Complement System : Lectin Pathway

The Complement System: Classical Pathway

Secondary Lymphoid Tissue

The Hematopoietic Microenvironment