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276 Part III Immunologic Basis of Hematology

those that function as an internal image of the original antigen The availability of safe IVIg preparations and the fortuitous
by mimicking the antigen structure, those that recognize antibody observation that IgG treatment of a patient with thrombocytopenia
combining site-associated idiotypes, and those that are specific for and IgG deficiency increased the patient’s platelet count began an
framework-associated determinants. The internal image antiidiotypic intense period of clinical use of IVIg for indications other than
antibodies are of clinical interest. primary immune deficiency. In 1990, the National Institutes of
Every immunoglobulin is a glycoprotein, and the critical glycan is Health sponsored a Consensus Development Conference, which
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attached to the H chain in the Fc domain at the conserved asparagine produced the first consensus statement on IVIg clinical indications.
at position 297 (Asn297). This single, N-linked glycan is essential for As a result, six disease indications—primary immunodeficiency,
maintaining an open conformation of the two H chains as it lines Kawasaki syndrome, chronic lymphocytic leukemia, human immu-
the opposing faces of the pair of C H2 subdomains of Fc (see Fig. nodeficiency virus (HIV) infections during childhood to prevent
24.8B). The core structure of the N-linked glycan is a biantennary infections, BM transplantation to prevent graft-versus-host disease or
heptapolysaccharide containing N-acetylglucosamine plus additional bacterial infections in adults, and idiopathic purpura—were approved
sugars (fucose, galactose), with bisecting N-acetylglucosamine and by the Food and Drug Administration (FDA) for labeling and mar-
sialic acid variably present. Effector functions depend on the Asn297- keting. The licensed indications remain unchanged, but off-label uses
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linked glycan and are influenced by its structure. Deglycosylated include more than 100 conditions (for further discussion, see Chapter
IgG does not interact effectively with Fcγ receptors (FcγRs) and 116). 160,161
cannot support in vivo effector responses, including antibody- The experience with IVIg clinical development has been largely
dependent cell-mediated cytotoxicity or complement-dependent empiric and anecdotal. The mechanisms for patient benefit or harm
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cytotoxicity. Individual glycoforms contribute to modulating are poorly understood, especially for high-dose immune modulation
inflammatory responses and have disease association. For example, therapy. Various known and some yet undiscovered functions of
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glycosylation differs in patients with rheumatoid arthritis or vascu- immunoglobulins in immune homeostasis may contribute, including
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litis compared with the normal population. Addition of sialic acid modulation of the function and expression of Fc receptors, interac-
to the N-linked glycan reduces binding of IgG to FcγRs and reduces tion with complement and cytokine systems, antiidiotypic antibodies,
in vivo cytotoxicity. Regulation of sialylation of IgG contributes and regulation of T-cell and B-cell function. 162–164
to the antiinflammatory homeostasis of serum IgG. Upon antigen Many effects of IVIg are explained by mechanisms beyond
challenge, reduced sialic acid–IgG can mediate immune clearance antigenic recognition of pathogens. IVIg preparations contain up to
and protective immunity through interaction with subclass-specific 30% dimers composed of idiotype–antiidiotype antibody pairs.
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FcγRs. Kaneko et al have proposed that the protective effect of These dimers appear to be very effective as a sink for activated
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intravenous immunoglobulin (IVIg) therapy is attributable to the complement and can inhibit complement activation. Benefit for
minor fraction of sialylated IgG species in the total IVIg prepara- treatment of immune thrombocytopenia purpura seems to be medi-
tion and that the high doses required (1–3 g/kg body weight) for ated by Fc-receptor blockade of the reticuloendothelial cell salvage
antiinflammatory activity could be significantly reduced by increasing receptor, also known as FcRn, combined with an antiidiotypic
the percentage of sialylated IgG. neutralization of antiplatelet antibody that together eliminates
antiplatelet antibody from the blood. Other indications of antibody
neutralization can be seen in IVIg treatment of myasthenia gravis.
THERAPEUTIC USE OF IMMUNOGLOBULIN The dramatic success of IVIg in treating Kawasaki syndrome may be
attributable to several mechanisms, including antiidiotypic neutral-
IVIg ization of antiendothelial antibodies, inhibition of cytokine produc-
tion and function, and elimination of causative superantigens. 166,167
IgG was one of the first plasma proteins prepared in a purified state IVIg inhibits B-cell activation and autoantibody production by
+
as a therapeutic drug for treatment of clinical disorders. It remains, enhancing CD8 suppressor T-cell function. Cell-mediated immunity
147
162
along with albumin and α-proteinase inhibitor, the most widely used is also affected. As mentioned earlier, Kaneko et al ascribe much
therapeutic plasma derivative and is currently the major plasma of the effect of IVIg to a small fraction of it that is sialylated. A 2011
product on the global market. Polyvalent human immunoglobulin report from this group suggests a mechanism for the way that
preparations have been used to reconstitute humoral immunity in sialylated IgG in IVIg downmodulates the inflammatory response of
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agammaglobulinemic patients for more than three decades. Until 30 the immune system. They suggest that the sialylated IgG Fc region
years ago, intramuscular treatment was the mode of administration. binds to DC-SIGN, a molecule on the surface of “regulatory”
Intramuscular preparations caused severe adverse reactions when myeloid cells, including DCs. In response to DC-SIGN ligation by
injected intravenously. 148–150 The most serious were anaphylactoid sialylated IgG, these cells secrete the cytokine IL-33, which in turn
reactions and were probably complement mediated. Efforts to reduce stimulates IL-4 production by basophils. IL-4 upregulates the syn-
anticomplementary activity and the prekallikrein activator activity thesis of the “inhibitory” class of FcγR on effector macrophages,
were initiated in the early 1980s and safer IVIg preparations became namely FcγRIIB. Because ligation of this class of FcγR by immune
available. complexes actually results in the recruitment of regulatory phospha-
Intravenous immunoglobulin is prepared from pooled human tases, which shut down intracellular signaling cascades, the net effect
plasma pools of 3000 to 50,000 L. The World Health Organization is to increase the activation threshold required to initiate inflamma-
requires more than 1000 donors per lot. The majority of IVIg tion by these effector cells.
is produced by cold ethanol fractionation procedures, 151,152 with
filtration and polishing chromatography steps added to increase
yield and decrease pathogen transmission. 153,154 Gamunex (Talecris Adverse Events Related to Intravenous
Biotherapeutics) is produced from cold ethanol fractionation fol- Immunoglobulin Infusion
lowed by caprylate precipitation and chromatograpy. 153,155 This
is the first significant change in commercial IVIg production in Adverse events associated with IVIg can be characterized as (1) early
20 years. IVIg contains concentrated IgG with normal plasma systemic events, (2) infectious disease transfer, and (3) high-dose
ratios of IgG1 and IgG2, lower percentages of IgG3 and IgG4, treatment-related adverse effects. 149
and only trace amounts of IgA and IgM. It retains the antibody
repertoire, reflecting the combined immunologic experience of the
donors. 156,157 Hyperimmune IVIg is purified from donor plasma Early Systemic Events
selected for high titer toward a specific pathogen. Prophylaxis for
cytomegalovirus and respiratory syncytial virus are two approved Common transfusion-related early events are listed in Table 24.3.
clinical applications. 157,158 Most early events are self-limiting and infusion rate dependent.