Page 1185 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1150 ParT TEN Prevention and Therapy of Immunological Diseases

Neutralizing Antibody Activity in IVIG Against superantigens, which could be used in the treatment of streptococ-
cal toxic shock syndrome. The neutralizing capacity of IVIG
Bacterial Toxins against these bacterial superantigens is important because of
Kawasaki syndrome (KS), an acute multisystem disease of their potential to stimulate the production of proinflammatory
unknown etiology, primarily affects infants and young children. cytokines that lead to clinical disease. A number of in vitro studies
Although KS occurs worldwide in children of all racial groups, have shown that IVIG can inhibit the production of, or bind to
it is most prevalent in Japan and in children of Japanese ancestry. and neutralize, a number of cytokines and growth factors from
Although the acute illness is generally self-limiting, coronary various cell types. 42-44 Thus IVIG may exert its antiinflammatory
artery abnormalities related to a generalized inflammation and effects in many different types of inflammatory diseases by
immune activation of small- and medium-sized blood vessels interrupting or modifying a number of different steps in the
develop in up to 25% of untreated patients. Although the etiology inflammatory cascade, from the inhibition of effector cell function
remains unknown, the clinical features and laboratory findings to reduction in cytokine-induced endothelial cell activation, or
suggest an infectious or postinfectious process. The administration the “neutralization” of proinflammatory cytokines.
of high-dose IVIG, together with aspirin, is the standard of care
in the treatment of KS.
KS is associated with marked activation of T cells and Modulation of Adhesion Molecules on
monocytes–macrophages. On the basis of immunological and Endothelial Cells and Antibodies in IVIG
clinical features of KS overlapping with those of bacterial toxic to Cell Surface Receptors
shock–like syndrome, studies were carried out to determine if IVIG contains a number of natural autoantibodies that may
KS is associated with exposure to a superantigen, such as a have immune-modulating activities (e.g., antibodies to CD4,
bacterial toxin. Acute KS is associated with marked immune major histocompatibility complex [MHC] class I molecules,
activation and increased circulating cytokine levels. Some of cytokines, adhesion molecules, and Siglec molecules on leukocytes
these cytokines elicit proinflammatory and prothrombotic and other cell surface molecules). The “natural” antibodies in
responses by inducing the expression of leukocyte adhesion IVIG have also been shown to bind to a number of plasma and
molecules, which localize inflammatory cells to vascular endo- tissue proteins, including B cell–activating factor (BAFF),
thelial cells. The expression of endothelial–leukocyte adhesion granulocyte macrophage–colony-stimulating factor (GM-CSF),
molecules has been demonstrated in acute KS, and its downregula- liver antigens, and beta-amyloid peptide. 42,45 The binding of native
tion correlates with favorable response to IVIG treatment. The IgG can be significantly increased by mild denaturing conditions
magnitude and persistence of proinflammatory cytokine synthesis (e.g., mild pH treatment and cold ethanol precipitation used
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have been reported to constitute a risk for the development of during the manufacturing of IVIG). St-Amour et al. suggested
coronary artery abnormalities. that these commercial fractionation processes for IVIG could
IVIG has been shown to contain high titers of specific antibod- contribute to its therapeutic antiinflammatory effects.
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ies inhibitory to the activation of T cells by staphylococcal and Vassilev showed that IVIG contains specific antibodies
streptococcal superantigens (Chapter 6). These findings may to a 10-peptide sequence, including the RGD (Arg-Gly-ASP)
account for the observation that treatment of acute KS with motif that is expressed in adhesion molecules on a variety
IVIG results in a marked reduction of macrophage and T-cell of cell surfaces. Most integrins bind to this RGD sequence.
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activation. In this regard, the efficacy of IVIG in suppressing Gill et al. reported that IVIG inhibits leukocyte recruitment
the immune activation associated with KS and, more importantly, into inflammatory tissues by inhibiting selectin and integrin
its ability to prevent the development of coronary artery abnor- binding. In a mouse model of sickle cell vaso-occlusive crisis,
malities in this illness may relate to the neutralizing antibody IVIG was shown to inhibit neutrophil adhesion to the vascular
activity of IVIG against these bacterial toxins. Toxin neutralization endothelium, resulting in an increase in capillary blood flow
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is not likely the only beneficial effect of IVIG in KS. Blocking and reversal of the vessel occlusion. IVIG could modulate this
or neutralizing cytokines by the anticytokine antibodies in cytokine-mediated endothelial cell activation by neutralizing the
IVIG may modulate the local inflammatory responses of effects of the cytokines, inhibiting endothelial cell responses to the
blood vessels in KS by modifying leukocyte adhesion after cytokines, or inhibiting the production of cytokines and growth
increasing the expression of cell-surface determinants on vascular factors. These mechanisms of IVIG may be playing an important
endothelial cells. role in preventing coronary artery abnormalities in patients
IVIG may have therapeutic value in the treatment of patients with KS.
with toxic shock syndrome secondary to Staphylococcus aureus Toxic epidermal necrolysis (TEN) and Stevens-Johnson
or Streptococcus pyogenes exotoxins. In an open study by the syndrome (SJS) are severe drug-induced skin diseases (reviewed
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Canadian Streptococcal Study Group , IVIG appeared to be in Letko et al. ). TEN results in apoptotic epidermal cell death,
beneficial in patients with streptococcal toxic shock syndrome. in which there is separation of large areas of the skin at the
In a meta-analysis of IVIG treatment of neonatal sepsis, there epidermal junction, producing the appearance of scalded skin.
was a sixfold decrease in mortality. IVIG inhibits Staphylococcus Keratinocyte apoptosis that precedes epidermal detachment is
exotoxin–induced T-cell activation and contains antibodies against an early event in TEN. A number of drugs, including sulfonamides,
exotoxins responsible for toxic shock syndrome. Great variations anticonvulsants, and NSAIDs, can cause TEN and SJS. The
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in neutralizing activity against streptococcal pyrogenic exotoxins mortality rate can be as high as 30%. Viard et al. studied serum
can be found in different brands and even among different lots samples from patients with TEN and found that the sera of these
of IVIG. However, these findings suggest that it is possible to patients had very high levels of soluble Fas ligand (sFasL).
select one IVIG preparation that contains high levels of neutral- Keratinocytes normally express the death receptor Fas. The
izing activity against a wide variety of Group A streptococcal keratinocytes of patients with TEN also express very high levels