Page 1186 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 84 Immunoglobulin Therapy: Replacement and Immunomodulation 1151

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of active Fas ligand. In their small pilot study, Viard et al. model downregulated the Th-17 pathway. In patients with KS
administered IVIG (0.2–0.75 g/kg for 4 consecutive days) to 10 and GBS, clinical improvement with IVIG therapy correlated
patients with TEN. In all 10 patients, the progression of skin with increased number and function of Tregs. 63,64
disease was rapidly arrested within 24–48 hours, with rapid skin
healing and no adverse effects. In in vitro studies, IVIG completely Summary: IVIG in Treatment of Autoimmune and
inhibited Fas-mediated keratinocyte apoptosis. This effect was Inflammatory Diseases
related to the presence of naturally occurring Fas-blocking Clearly, IVIG (IgG) has a number of immune-modulating effects
antibodies in IVIG, which inhibit Fas-mediated keratinocyte cell and has been found to be an effective treatment for a wide
death. spectrum of autoimmune and inflammatory diseases. 44,65 At
present, IVIG is FDA approved for only a few autoimmune and
Modulation of Complement Effector Function inflammatory diseases. In autoantibody-mediated disease, the
The principal inflammatory mechanism in dermatomyositis Fc domain appears to be the important IgG moiety that leads
(DM) is complement (C)-dependent microangiopathy with to immune modulation. The importance of sialylation of the
activation of C3 and deposition of the complement C5b-9 Fc fragment remains controversial, as do the mediators involved
membrane attack complex (MAC) on the endomysial capillar- (e.g., IL-33 and IL-4). Differences in animal models, IVIG source,
ies. 26,52 Basta et al. showed that IVIG can inhibit the uptake of route and timing of the administration of the IVIG, mouse strain,
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C components on target tissues. In patients with DM who were and other variables may account for the differences in the
treated with IVIG, C3 deposition was reduced with corresponding experimental observations of laboratories. In T-cell mediated
decreases in complement expression on endomysial capillaries. 26,52 animal models of disease, such as EAE, there is strong evidence
IVIG prevents the uptake of complement components and that there is upregulation of Tregs and inhibition of the Th17
formation of the MAC on the endomysial capillaries in the muscle pathway. These effects may be mediated by the F(ab’)2 portion
tissues of patients with DM. Consequently, IVIG allowed neo- of the IgG molecule, and not the Fc domain. Furthermore, there
vascularization to occur with reversal of the ischemic process, is also controversy over the receptor on antigen-presenting cells
resulting in muscle tissue healing. This effect of IVIG on comple- (APCs), such as macrophages and DCs, which are involved in
ment deposition may be relevant to other autoimmune neurologi- the immune-modulating process mediated by IVIG. In certain
cal diseases, such MG, GBS, and CIDP, in which complement animal models, the SIGN-R1 (or in humans DC-SIGN) is
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may be playing a role in the tissue damage. 26,52 Arumugam et al. important, and in other models (e.g., murine asthma), a novel
showed that IVIG protects the brain against ischemic injury C-type lectin receptor (DCIR) appears to be important. These
mediated by complement in a mouse model of experimental differences undoubtedly relate to the disease model. Two studies
stroke. have demonstrated the importance of the PGE 2 pathway on
IVIG-induced immune modulation mediated by the F(ab’)2
Effects of Ig on the Regulatory T-Cell Pathways portion of the IgG molecule. These observations may point to
In a mouse model of multiple sclerosis (MS), IVIG has been the possibility of alternative treatment regimens that employ
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shown to expand and enhance the function of FoxP3 regulatory the selective increase in PGE 2 in certain autoimmune or inflam-
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T cells (Tregs) while inhibiting the differentiation of T-helper matory disorders to increase Tregs and inhibit the production
17 (Th17) and Th1 cells. This protective effect of IVIG was of certain cytokines. Further clarification in human disease models
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lost in mice that were depleted of Tregs. These changes were using in vitro human cells is important. These mechanisms are
independent of FcγRIIB and the Fc domain, since F(ab’) 2 frag- not mutually exclusive, and probably more than one mechanism
ments led to similar changes in Th17 cells, Tregs, and clinical is playing a role in the efficacy of Ig therapy in an autoimmune
efficacy in this experimental allergic encephalomyelitis (EAE) disease process. A better understanding of the pathogenic
model. Desialylated IVIG had the same immune-modulating mechanisms involved in these diseases will undoubtedly lead to
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effects as “native” IVIG. Investigations by Trinath et al. sug- a more effective therapy with IVIG and more specific, modified
gested that the mechanism by which IVIG induces Tregs was forms of this biological product.
the enhancement of the cyclooxygenase 2 (COX-2) pathway
via increased expression of prostaglandin E2 (PGE 2 ) from
human DCs.
Kaufman et al. have extensively studied the effects of IVIG ON THE HOrIZON
therapy in an ovalbumin-sensitized mouse model of asthma. Translational Research Opportunities Related to
They reported that IVIG markedly attenuated lung inflammation, Immunoglobulin Therapy
decreased bronchial hyperresponsiveness to methacholine, and
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suppressed the Th2 pathway. The draining pulmonary lymph • Elucidation of mechanism(s) of action will lead to more precise bio-
nodes of IVIG-treated mice showed a significant increase in engineered molecular products to treat autoimmune and inflammatory
diseases.
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CD4 CD25 FoxP3 regulatory cells. IVIG-primed DCs on adoptive • Clarification of the mechanisms of action of intravenous immunoglobulin
transfer to ovalbumin (OVA)–sensitized and challenged mice (IVIG) in autoimmune and inflammatory diseases should lead to better
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abrogated airway hyperresponsiveness and induced Tregs. In understanding of the pathobiology of these diseases.
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their model system, Massoud et al. reported that sialylated IgG • Enhanced product purification—identification of the minor components
bound to a novel C-type lectin receptor (i.e., dendritic cell in Ig products that may contribute to adverse reactions should lead
immunoreceptor [DCIR]) induced Tregs. Thus a number of to improved manufacturing processes and improved product tolerability
studies have demonstrated the importance of the induction for patients (e.g., procoagulant factors, isohemagglutinins)
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of FoxP3 Tregs by IVIG in modulating the autoimmune/ • Ig delivery—development of innovative approaches to the delivery of
Ig products to patients to enhance safety and compliance.
antiinflammatory process. In contrast, Ig therapy in this murine