Pharmacology

The pharmacology of immunoglobulins is discussed in detail by D.wY®L(19.9.2..). Structure and function of immunoglobulins

The five immunoglobulins classes (IgA, IgD, IgE, IgG, IgM) produced during the humoral immune response have a similar Y-shaped structure with two heavy and two light chains. Each chain consists of a variable and a constant region. Within the variable region is an idiotypic hypervariable or complementarity-determining region (CDR) that binds a unique antigenic determinant. The constant region binds to complement components and Fc receptors on the surface of macrophages, lymphocytes, neutrophils, and eosinophils.

Immunoglobulin preparations

Standard non-specific intravenous immunoglobulin preparations prepared from pooled normal human plasma have been available since the early 1980s. Each manufacturer uses its own donor pool and every batch consists of at least 2000 donors. IgG is the principal class, although IgM and IgA may be present. Various preparations differ in the method of processing, formulation, pH, osmolarity, IgG subclass composition, and antibody titers. All contain antibodies against a variety of micro-organisms. Hyperimmune IgG preparations from donors with high specific neutralizing antibody titers (naturally acquired or following immunization) and immunoglobulin specifically enriched with IgM are also available.

Mechanism of action

In immunosuppressed critically ill patients at high risk of infection, human intravenous immunoglobulin containing a diversity of antibodies that neutralize specific bacterial organisms or products such as lipopolysaccharide has been postulated to enhance the immune response to infection. Antimicrobial effects include enhanced opsonization, complement activation, and antibody-dependent cell cytotoxicity.

The acute inflammatory response may also be attenuated by the selective modulation of cytokine synthesis. An increased ratio of anti-inflammatory mediators (soluble tumor necrosis factor-a receptor and IL-1 receptor antagonist) to proinflammatory mediators (IL-1b, tumor necrosis factor-a, IL-6, and IL 8) has been demonstrated.

In primary humoral immunodeficiencies, intravenous immunoglobulin replaces deficient IgG. In other immunohematological disorders suggested mechanisms of action include the following:

1. competitive blocking of macrophage IgG Fc receptors by the immunoglobulin Fc portion (prevents autoantibody binding and ingestion of IgG-coated cells);

2. inhibition of active C3 fragment binding to target cells and complement-dependent clearance;

3. binding of infused anti-idiotypic antibodies to the autoantibody idiotypic region (increases complex clearance by the reticuloendothelial system) and to the autoantibody-producing B cell (downregulates autoantibody production).

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