Page 1183 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1148 ParT TEN Prevention and Therapy of Immunological Diseases

Other Adverse Reactions KEY CONCEPTS 3
A number of other adverse reactions have been reported in Mechanisms of Action of Intravenous
association with IVIG infusions. (Clinical Pearls 2) These side Immunoglobulin (IVIG) in Autoimmune and
effects are usually less common and are discussed in more detail Inflammatory Diseases
elsewhere. 21
• Blockade of Fc receptors on macrophages of the reticuloendothelial
system of liver and spleen
Summary: Ig Replacement in Treatment of • Restoration of idiotypic/antiidiotypic network
Immune Deficiency • Suppression or neutralization of cytokines by specific antibodies in
Ig replacement is the mainstay of treatment for primary humoral the IVIG
immune deficiency. The goal of treatment is to provide a broad • Block binding of adhesion molecules on leukocytes to vascular
endothelium
spectrum of antibodies to prevent infections and chronic • Inhibition of complement uptake on target tissues
long-term complications. The usual dose is 400–600 mg/kg/ • Neutralization of microbial toxins
month, but this may vary among individuals, and some patients • Blockade of Fas ligand mediated apoptosis by anti-Fas antibodies in
may require higher doses. A serum trough level above 500 mg/ the IVIG
dL has been shown to be effective in the prevention of • Induction of apoptosis with anti-Fas antibodies at high concentrations
serious bacterial infections. However, recent studies have sug- of IVIG
gested that even higher doses (e.g., a “biological” trough level • Neutrophil apoptosis by anti-Siglec-9 antibodies in IVIG
and achieving trough levels of IgG in the range of 750–900 mg/ • Saturation of FcRn receptors to enhance the clearance of
autoantibodies
6
dL) may be desirable. Ig can be given intramuscularly, • Induction of inhibitory FcγInd receptors on effector macrophages
intravenously, or subcutaneously. SC administration has been • Neutralization of growth factors for B cells (e.g., B cell–activating
proven to be safe and is a good alternative in some patients, factor ([BAFF])
especially those experiencing side effects of administration by • Inhibition of T-cell proliferative responses
the IV route. Generally, IVIG replacement therapy is considered • Expansion and/or activation of a population of regulatory T cells (Tregs)
safe in the majority of patients. Side effects are usually mild and • Enhancement of the cyclooxygenase 2 (COX-2) pathway by increasing
prostaglandin E2 (PGE 2 ) from dendritic cells (DCs)
treatable with premedication. Good manufacturing practices, • Downregulation of the T-helper 17 (Th17) pathway
improved screening of plasma donors, testing of the source • Modulation of DC function through C-type lectin receptors (DCLRs)
plasma, and additional viral inactivation and removal steps have DC-specific intercellular adhesion molecule-grabbing nonintegrin
made IVIG a better and safer plasma-derived product. To (DC-SIGN; spleen) and DCLR (lung and lymph nodes)
optimize the care of patients with PIDs, there are eight guiding
principles for the use of Ig replacement therapy. (see Therapeutic
Principles) have shown that IVIG leads to the rapid reversal of the throm-
bocytopenia. Autoantibody-opsonized platelets are destroyed in
the spleen and the liver by FcγR-mediated phagocytic clearance.
MECHANISMS OF ACTION OF IG (Key Concepts 4)
THERAPY IN AUTOIMMUNE AND
INFLAMMATORY DISEASES Interactions of Idiotype and Antiidiotype as
Immune Modulation
Although we still do not understand all the mechanisms by which Idiotype–antiidiotype interactions between antiplatelet glyco-
IVIG has immunomodulatory effects, knowledge of the actions protein IIb (GPIIb)/IIIa autoantibodies and IVIG may be another
of IVIG in these diseases will allow for definition of appropriate mechanism by which IVIG could affect autoantibody production
indications and schedules of administration of IVIG and the and effector function in ITP and may be playing a role in the
design of new-generation IVIG products that are better able to long-term immune effects in ITP. IVIG contains antiidiotypic
target the immune perturbations in autoimmune and inflam- antibodies to anti-DNA, anti–factor VIII, antineutrophil cyto-
matory processes. (Key Concepts 3) Furthermore, additional plasmic antibody (ANCA) autoantibodies, antithyroid autoan-
multicenter placebo-controlled clinical trials are needed to confirm tibodies, and others. A proposed mechanism of action of IVIG
clinical efficacy. A more detailed discussion of the evidence-based in ANCA-positive vasculitis is binding or neutralization of the
treatment of autoimmune and inflammatory disorders can be ANCA autoantibodies by antiidiotypic antibodies in IVIG. Studies
1,2
found elsewhere. This chapter will not review the indications have shown that IVIG contains antibodies with idiotypic specifici-
for IVIG therapy; the reader is directed to other works, including ties that can bind and neutralize potentially pathogenic auto-
comprehensive reviews and practice-based guidelines, for more antibodies in autoimmune neurological diseases, such as
details about the various indications for IVIG therapy in Guillain-Barré syndrome (GBS), chronic inflammatory demy-
26
autoimmune and inflammatory disorders. This section will address elinating polyneuropathy (CIDP), and myasthenia gravis (MG).
the possible mechanisms of actions of Ig therapy; more than Antiidiotypic antibodies in IVIG directed against idiotopes on
one mechanism(s) may be important in the immune modulation the anti-GM 1 Ig molecule block the binding of the anti-GM 1
of these autoimmune disorders. antibodies to its target antigen. Support for a similar mechanism
in MG comes from the fact that IgG or F(ab’) 2 fragments in
Blockade of Fc Receptors of the IVIG preparations are capable of binding to anti–acetylcholine
Reticuloendothelial System receptor antibodies in vitro. Additionally, using in vitro nerve-
27
Idiopathic thrombocytopenic purpura (ITP) results from acceler- muscle preparations, Buchwald et al. showed that the F(ab’) 2
ated platelet destruction attributable to an immunological process portion of IVIG neutralized the “blocking” effect of serum from
resulting in bleeding that may be life threatening. Studies in ITP patients with acute GBS. (Key Concepts 5)