Download High dose intravenous immunoglobulin treatment: Mechanisms of

REVIEW
High Dose Intravenous Immunoglobulin Treatment:
Mechanisms of Action
Peter Boros,1 Gabriel Gondolesi,1 and Jonathan S. Bromberg1,2
Intravenous immunoglobulin (IVIg) treatment was introduced as replacement therapy for patients with antibody
deficiencies, but evidence suggests that a wide range of
immune-mediated conditions could benefit from IVIg. The
immunoglobulins are precipitated from human plasma by
fractionation methods. In conclusion, the differences in basic
fractionation methods and the addition of various modifications for purification, stabilization, and virus inactivation
result in products significantly different from each other.
(Liver Transpl 2005;11:1469-1480.)
patient and are believed to correct immune dysregulation. Immunomodulatory and anti-inflammatory
properties associated with IVIg administration are
based on multiple connected and synergistic mechanisms.
Here, we review the potential immunologic mechanisms of action, with particular emphasis on the use of
IVIg in organ transplantation.
The mode of action of IVIg depends largely on antigen
binding and modification of effector functions. Antigen
binding is mediated via immune antibodies and a wide
spectrum of autoantibodies. The effector functions
include modulation of expression and function of Fc
receptors, complement activation, complement binding,
anti-inflammatory effects ensuing from interference with
the cytokine network, provision of anti-idiotypic antibodies, and modulation of T- and B-cell activation. Organ
transplantation is an important field for IVIg treatment,
primarily for patients with high titers of anti-HLA antibodies.
Intravenous immunoglobulin (IVIg) treatment was
introduced in the 1950s as replacement therapy for
patients with congenital antibody deficiencies. Clinical
and experimental evidence accumulated since then suggests that a wide range of immune-mediated conditions
could benefit from IVIg, including acute and chronic/
relapsing diseases, autoimmune diseases mediated by
pathogenic autoantibodies, or by autoaggressive T cells, as
well as inflammatory disorders. IVIg treatment of immunodeficiency delivers missing immune antibodies against
pathogens. This form of treatment is aimed at substitution
or passive immunization against multiple bacteria and
viruses. The use of IVIg in hyperactive conditions of the
immune system is not as widely accepted, although the
efficacy of IVIg treatment has been demonstrated in several autoimmune diseases.1-4
IVIg preparations are fractionated from a plasma
pool of healthy donors and contain both immune antibodies and physiologic autoantibodies. As immune
antibodies reflect the immunologic experience of the
donor population, this component is utilized for
replacement therapy and passive immunization. Natural autoantibodies react with the immune system of the
Production and Properties of IVIg
Preparations
Several different IVIg formulations are licensed in the
USA and Europe. The production process might affect
composition and properties, alter tolerability, and ultimately modify therapeutic effects. IVIg is prepared
from pools of plasma from up to 100,000 (a minimum
of 3,000) healthy blood donors, and it is assumed that
IVIg contains the entire array of variable regions of
antibodies that would be present in normal serum. The
large number of donors in the pool adds more individual activities to the IVIg preparation; however, it carries
the risk of diluting out any useful activity that is rare.
Preparation of IVIg
The immunoglobulins are precipitated from human
plasma by fractionation methods using ethanol. While
Abbreviations: IVIg, Intravenous immunoglobulin; HIV,
human immunodeficiency virus; HTLV, human T cell lymphotropic
retrovirus; GPI glycosylphosphatidylinositol; Th1, T helper 1;
IL-1ra, interleukin-1 receptor antagonist; IL-1, interleukin-1; HBV,
Hepatitis B virus; CMV, Cytomegalovirus; CIg, Cytomegalovirus
immunoglobulin.
From the 1Recanati/Miller Transplantation Institute, The Mount
Sinai School of Medicine, New York, NY; and 2Department of Gene and
Cell Medicine, The Mount Sinai School of Medicine, New York, NY.
Received March 15, 2005; accepted August 17, 2005.
Address reprint requests to Peter Boros, Recanati/Miller Transplantation Institute, The Mount Sinai School of Medicine, POB 1504, New
York, NY, 100229-6574. Telephone: (212) 241-5589; FAX: (212)
426-2233; E-mail: [email protected]
Copyright © 2005 by the American Association for the Study of
Liver Diseases
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/lt.20594
Liver Transplantation, Vol 11, No 12 (December), 2005: pp 1469-1480
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Boros et al.
the early products could not be administered intravenously as they contained aggregates and other impurities capable of activating complement and causing
severe reactions, processing modifications developed
over the years ensure the stability and purity of preparations.5 Today’s IVIgs, suitable for intravenous administration, contain high levels of intact IgG, display normal distribution of IgG subclasses, and have only small
concentrations of dimers. Further modifications
involving specific virus inactivation or removal (solvent/detergent treatment, low pH incubation, ultrafiltration, and pasteurization) made these products even
safer.
The differences in basic fractionation methods and
the addition of various modifications for purification,
stabilization, and virus inactivation resulted in products
significantly different from each other with respect to
chemical structure, antibody content, subclass distribution, and electrophoretic profile. When commercial
products are compared for antibody activity to various
bacteria such as Staphylococcus aureus, Pseudomonas
aeruginosa, Escherichia coli, and group B Streptococcus,
they were found to have differences and inconsistencies
among batches and formulations, with some of the
products showing reduced opsonization activity.6-8
Different production procedures have also been shown
to affect Fc receptor activity9 or complement fixation,10
which can influence the protective effects of IVIg in
patients with antibody deficiency. These factors may
significantly affect clinical outcome in treated patients.
There is an important distinction between standard
pooled IVIg (derived from the plasma of unselected
normal donors) and hyperimmune immunoglobulins.
To prepare hyperimmune immunoglobulins, donors
are selected for high levels of reactivity to specific pathogens. Those samples are specially selected, pooled, and
immunoglobulin derived from them is used to manufacture specific products to treat or prevent diseases
such as cytomegalovirus, respiratory syncytial virus,
hepatitis B, tetanus, and varicella.
Properties of IVIg Preparations
General Characteristics
The Food and Drug Administration currently approves
eight IVIg preparations for use in the United States.
Preparation methods as mentioned vary somewhat, but
the final product is purified IgG, with traces of IgM.
Half-lives, may range from 21 to 33 days, and pH may
also vary, which may be relevant for acid-base balance in
certain patients. Products can also differ with respect to
the composition of stabilizers (e.g., maltose, sucrose,
and mannitol), which may significantly affect their
osmolality. Some IVIg preparations are shipped in liquid form, while others are shipped in lyophilized form
and reconstituted at the time of infusion.
The risk of transmission of infectious disease is a
concern whenever blood derivatives are prepared from
large numbers of donors. Safety standards for viral
pathogens include plasma testing of both individual
donations and pools, all products are tested for human
immunodeficiency virus (HIV), hepatitis B, hepatitis
C, and human T cell lymphotropic retrovirus (HTLV).
Solvent/detergent treatment inactivates enveloped
viruses, such as HIV, while several other aggressive processing steps including treatment with trypsin, pasteurization, nano-filtration, and low pH are used to remove
or inactivate additional pathogens. These steps are complementary and increase overall safety by providing the
widest possible safety margin against known and
unknown viruses. Wide variations have been reported
regarding the risk of transmission of hepatitis C. Some
preparations, including Gammagard and Polygam,
both prepared by fractionation and chromatographic
purification, were implicated in over 100 cases worldwide.11 Today, validated industrial-scale viral inactivation and removal methods mentioned above are being
used in the manufacturing processes of the available
IVIg preparations. Combined with vigorous donor
screening, plasma testing, and quality control procedures, these steps have greatly minimized the risk of
hepatitis C transmission.12
Components
Sugar Content
To prevent aggregate formation, sugars such as sorbitol,
glucose, and sucrose are added to IVIg preparations.
The major, albeit rare, complication associated with
sugar content is acute renal failure or insufficiency as
more than 90% of the IVIg-associated adverse renal
events in the United States occurred with sucrose-containing IVIg preparations.13 Nephrotoxicity can be a
serious complication of IVIG therapy. Preexisting renal
disease, volume depletion, and old age are risk factors
for such toxicity. A recent analysis reported that a high
percentage of these patients required hemodialysis, and
mortality occurred in 10-15%.14
Sodium Content
The sodium content, ranging from trace amounts to
0.9%, determines the osmolality of the infused solution
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IVIg Treatment
Table 1. IVIg Products
Sugar
content
Product
Manufacturer
Viral inactivation
IgG
IgA
IgM
pH
Venoglobulin-S
solvent/detergent
⬎99%
15–20 ␮g/ml
10–40 ␮g/ml
5.2–5.8
Panglobulin
Alpha
Therapeutic
ARC
ⱖ96%
⬎970 ␮g/ml
⬎20 ␮g/ml
6.4–6.8
Polygam
ARC
pH 4, pepsin,
filtration
solvent/detergent
5% Dsorbitol
5% sucrose
ⱖ90%
⬍3.7 ␮g/ml
trace
6.4–7.2
2% glucose
Gammagard
Baxter
Healthcare
Bayer
solvent/detergent
ⱖ90%
⬍3.7 ␮g/ml
trace
6.4–7.2
2% glucose
pH 4.2, solvent/
detergent
Pasteurization
ⱖ98%
trace
trace
4–4.5
None
ⱖ98%
25–50 ␮g/ml
20–50 ␮g/ml
6.4–7.2
5% sucrose
trypsin, PEG
100%
⬍2 ␮g/ml
trace
6.4–6.8
5% glucose
pH 4, pepsin,
filtration
ⱖ96%
⬍970 ␮g/ml
⬍20 ␮g/ml
7
5% sucrose
Gamimmune
Gammar-P
Iveegam
Carimmune
Aventis
Behring
Baxter
Healthcare
ZLB
Bioplasma
and thus can affect tolerability and occurrence of
adverse events.
Osmolality
Osmolality in different IVIg solutions may range from
physiologic values (280-296 mOsm/l) to greater than
1,000 mOsm. Hyperosmolar solutions may cause fluid
shifts and the occurrence of infusion-related adverse
events.
pH
The optimal pH to prevent aggregation is 4.0 to 4.5.
Low-pH preparations are instantaneously neutralized
by the buffering capacity of blood on infusion. Many
IVIg products have a final pH that is close to neutral (a
pH of 7.0-7.5) or in the range of 6 to 7, requiring the
addition of different agents to maintain stability and
prevent aggregation.
IgA Content
A principal clinically significant difference among IVIg
products is the presence or absence of IgA. Some
patients are IgA-deficient, so it is extremely important
that their IgA levels be measured before receiving the
first IVIg treatment. IgA-deficient patients may develop
immunity to IgA and are at increased risk of anaphylaxis
if they receive a blood product that contains IgA. Several methods have been developed to prevent anaphylaxis; both ex vivo pretreatment of the IVIg preparation
with autologous plasma or subcutaneous injection of
the IVIg allow safe management of patients even with
high anti-IgA titers.15,16
Osmolarity
300–330
mOsm/l
192–768
mOsm/l
663–1,326
mOsm/l
636–1,250
mOsm/l
274 mOsm/l
330–600
mOsm/l
375 mOsm/l
192–768
mOsm/l
Isohemagglutinin Antibodies
Preparations of IVIg contain low titers of anti-A,
anti-B, anti-C, and anti-E blood group antibodies.
Mild, self-limiting hemolysis due to residual anti-A and
anti-B antibodies may regularly occur. Serious hemolysis has been reported only with hyperimmune preparations.17 Table 1 summarizes some of the main characteristics of primary IVIg products.
Mechanisms of Action of IVIg
The extensive range of effects associated with IVIg treatment reflects the functions of circulating immunoglobulins in the maintenance of tolerance to self and immune
homeostasis in healthy individuals. The mode of action of
IVIg is complex, but efficacy depends on two general types
of mechanism: antigen binding and modification of various effector functions. Antigen binding is mediated by the
Fab part. The effector functions include binding to the
various Fc receptors resulting in modulation of expression
and function of Fc receptors, complement activation,
complement binding, anti-inflammatory effects resulting
from interference with the cytokine network, provision of
anti-idiotypic antibodies, and modulation of T and B-cell
activation.1-4,18-23 It should be emphasized that these
mechanisms overlap, and the outcome of IVIg treatment
manifests as a combination of many different effects.
Antigen Binding
Natural Antibodies
These antibodies are mostly IgM, but can also be of
the IgG or IgA classes, and are not the result of an
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immune response because they are also present in
embryos as well as in animals raised under sterile
conditions.24,25 Natural antibodies have been shown
to prevent the spreading of pathogens into the brain
and the kidneys, and can therefore be considered as
“first-line defense” antibodies, and elements of the
innate immune system.26 Natural autoantibodies can
be autoreactive and be part of the “first-line defense”
at the same time. The peripheral control of natural
autoantibody production occurs through their Fab
portions or idiotypes. In turn, these Fab parts are
recognized by other natural anti-idiotypic autoantibodies. Natural autoantibodies bind to both pathogens and complement factors, and promote the
uptake of pathogens by antigen-presenting cells.
Consecutively, this may facilitate an effective adaptive immune response against pathogen-specific
epitopes, while the development of autoimmunity is
prevented.27
CD4-positive T cells by human immunodeficiency
virus.33 Natural anti-MHC class I antibodies block the
function of CD8 T cells in vitro.34
Natural “First-Line Defense” Antibodies
Sera of healthy individuals, and therefore all IVIg preparations, contain physiologic autoantibodies directed
against an wide range of cytokines (IL-6, IL-1, TNF-␣,
IL-8, and GM-CSF).41-43 These antibodies are partially
responsible for the anti-inflammatory activities of IVIg
by neutralizing pro-inflammatory cytokines.
Superantigens may trigger the activation of autoreactive
cells in an MHC unrestricted manner. IVIg contains
antibodies to superantigens such as TSST-1 and Staphylococcal enterotoxins. Autoimmune diseases have
often been associated with bacterial or viral superantigens, which may accelerate such conditions. Thus,
anti-superantigen antibodies can be considered as
immunomodulatory resulting in the elimination of
pathogens.28
Physiologic Autoantibodies Against AntigenBinding Structures
IVIg may contain natural autoantibodies directed
against the idiotype, the hinge region, the constant
heavy chain 1, and the constant light chain domains of
antibodies. The anti-idiotype antibodies bind pathogenic autoantibodies in vitro, suggesting that they
might also be able to prevent binding to autoantigens
under in vivo conditions.29,30 Anti-idiotype autoantibodies may also bind to variable regions of antigen
receptors, rendering B and T cell activation by autoantigens impossible. Physiologic autoantibodies against
the variable region of the T-cell receptor block autoantigen-mediated T-cell activation resulting in long-term
T-cell down-regulation.31,32
CD4 and MHC Class I-Specific Autoantibodies
Natural autoantibodies against both CD4 and MHC
class I have been detected in IVIg preparations. In vitro,
natural anti-CD4 antibodies block T-cell proliferation
in mixed lymphocyte cultures and the infection of
Autoantibodies Against the Fas Receptor
IVIg preparations contain natural anti-Fas receptor
autoantibodies that block Fas ligand/Fas receptor interactions and prevent keratinocyte apoptosis.35,36 This
explains the beneficial effects of IVIg treatment in
patients with toxic epidermal necrolysis, a condition
where keratinocytes are highly sensitized toward Fas
ligand-mediated apoptosis.37 The titers of Fas inhibitory antibodies vary from batch to batch similar to the
anti-microbial antibodies. Agonistic anti-Fas receptor
autoantibodies have also been detected in IVIg preparations.38 These antibodies might support anti-inflammatory effects by promoting apoptosis of activated T
cells or neutrophils.39,40
Cytokine-Specific Natural Autoantibodies
Effector Functions
IVIg preparations have been shown to exhibit antiinflammatory properties in patients with diseases associated with a hypersensitive immune system. Many in
vitro and also in vivo data suggest a number of potential
mechanisms of action.
Activation/Blockade of Fc Receptors
IgG Fc receptors (Fc␥Rs) are immunoglobulin superfamily members and are of 3 main types: Fc␥RI
(CD64), Fc␥RII (CD32), and Fc␥RIII (CD16). All of
these are integral transmembrane glycoproteins, with
the exception of Fc␥RIIIB, which is expressed as a glycosylphosphatidylinositol (GPI)-linked molecule on
neutrophils. Most of the Fc␥Rs are of the activating
type, and receptor engagement leads to a variety of
functions depending on the type of effector cell, including phagocytosis, degranulation, antibody-dependent
cell-mediated cytotoxicity, cytokine release, and regulation of antibody production. Importantly, both mice
and human beings also express the inhibitory Fc␥R,
Fc␥RIIB, which contains inhibitory motifs in the cytoplasmic domain, and whose ligation down regulates
these cellular functions. Humans express other forms of
Fc␥RII, namely, Fc␥RIIA and Fc␥RIIC, that deliver
IVIg Treatment
activating signals, while mice express only the inhibitory form, Fc␥RIIB.44-47 IgG molecules bind via their
Fc region to Fc receptors on macrophages, neutrophils,
eosinophils, platelets, mast cells, natural killer cells, and
B cells. The Fc region of the antibody interacts with
hematopoietic cells to disable or up-regulate cellular
activities depending on the Fc receptor types. It is
widely accepted that treatment of idiopathic thrombocytopenic purpura and other autoantibody-induced
cytopenias by IVIg is mechanistically mediated by the
blockade of the Fc receptor on macrophages, which
prevents the removal of sensitized platelets by the
reticuloendothelial system.48
Attenuation of Complement-Mediated
Damage
IVIg binds the activated components C3b and C4b in a
C1q-independent and C1q-dependent fashion. By
scavenging these active complement components and
diverting complement attack from cellular targets, IVIg
prevents the generation of the C5b-9 membrane attack
complex, the deposition of the complex on target surfaces, and subsequent complement-mediated tissue
damage.49 In addition, natural anti-C3b autoantibodies
have been identified that inhibit C3 convertase activity
in vitro.50 This mode of action of IVIg is of significance
in the treatment of patients with severe dermatomyositis, Guillain-Barre syndrome, and myasthenia gravis.
Neutralization of Pathogenic Autoantibodies
and the Regulation of Autoreactive B-Cell
Clones
Inhibition of autoantibody activity by IVIg has been
observed in the case of autoantibodies to factor VIII,
thyroglobulin, DNA, intrinsic factor, peripheral nerve,
cytoplasmic antigens of neutrophils, platelet gpIIb/IIIa,
the acetylcholine receptor, endothelial cells, phospholipids, nephritic factor, and retinal autoantigens.51.
Presence of anti-idiotypes to disease-associated autoantibodies may be relevant in explaining the efficacy of
IVIg in myasthenia gravis, Lambert-Eaton myasthenia
syndrome, and antibody-mediated neuropathies.52
Induction of Anti-Inflammatory Cytokines
Modulation of the production of cytokines and cytokine antagonists is a major mechanism by which IVIg
exerts its anti-inflammatory effects in vivo in various
neuromuscular disorders such as inflammatory myopathies, demyelinating neuropathies, and myasthenia gravis.3,4. The anti-inflammatory effects of IVIg involving
modulation of cytokine production are not restricted to
monocytic cytokines but are also reliant on the ability of
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IVIg to increase T helper 1 (Th1) and Th2 cytokine
gene expression and production.53 IVIg selectively triggers the production of interleukin-1 receptor antagonist
(IL-1ra), the natural antagonist of interleukin-1 (IL-1),
in cultures of purified monocytes, without affecting the
production of the proinflammatory cytokines IL-1␣,
IL-1␤, IL-6, and TNF-␣.54
IVIg and Dendritic Cells
Alteration in the phenotype and function of dendritic
cells (DC) may explain, at least partially, the systemic
autoimmune responses that characterize systemic lupus
erhythematosus (SLE). HLA-DR⫹, CD4⫹ B7⫹ and
CD40⫹ DC are less frequent in SLE patients than in
control individuals. Functional analysis of DC from
SLE patients discovered diminished allogeneic and
antigen-specific T cell-stimulatory capacity compared
with healthy controls.55 IVIg interferes with the differentiation of DC from SLE patients and from healthy
donors cultured in the presence of SLE sera in vitro, and
reduces the capacity of mature DC to secrete IL-12
upon activation, while enhancing IL-10 production.
IVIg-treatment of DC also inhibits the ingestion of
nucleosomes by immature DC. IVIg induced downregulation of co-stimulatory molecules CD80/CD86
and modulation of cytokine secretion from DC, which
in turn resulted in the inhibition of auto-and allo-reactive T cell activation and proliferation.56,57 The inhibition of expression of co-stimulatory molecules on DC
by IVIg offers a possible explanation for the efficacy of
IVIg in other immuno-inflammatory conditions, such
as autoimmune diseases and transplantation.
Recent Advances in Understanding the
Mechanism of IVIg
Fc␥R-s with intracellular immune receptor tyrosinebased activation motifs (ITAM or activating receptors)
mediate inflammatory effector functions. Cytokines are
known to regulate Fc␥R expression on monocytes and
neutrophils. Th1 cytokines (TNF-␣ and IFN-␥) upregulate and activate various FcRs, while Th2 (IL-4 and
IL-13) cytokines up regulate the inhibitory FcR
(FcRIIB). IVIg induces both IL-4 and lL-13, and
induces FcRIIB leading to anti-inflammatory
effects.58,59 Thus, IVIg mediates in part its anti-inflammatory effect by up regulating the FcRIIB, which has a
negative effect on the inflammatory cascade (in contrast
to FcRI, III, IIA, and C). The importance of FcRIIb for
the therapeutic effect of IVIg has been directly suggested based on data from a mouse model of idiopathic
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thrombocytopenia. Fc␥RIIB was required for IVIg to
exert its protection, because disruption either by genetic
deletion or with a blocking monoclonal antibody
reversed the therapeutic effect of IVIg.60
IVIg may also influence the differentiation of new
monocytes/macrophages by IgG-IgG dimers, which
usually do not exist in the circulation, by shifting the
balance between inhibitory and activating receptors on
monocytes/macrophages. In hypogammaglobulinemic
patients with reduced occupation of Fc␥ receptors,
infusion of IVIg can result in the release of pro-inflammatory and subsequently anti-inflammatory cytokines.61,62 IgG-IgG dimers present in IVIg are responsible for this phenomenon and the absence of polymers
in IVIg preparations may prevent cytokine release.63
Dimers may be responsible for many adverse effects
associated with IVIg treatment.64-66
IVIg have also been reported to accelerate autoantibody catabolism by binding to an Fc receptor called
“FcRn” on endothelial cells. If IgG is pinocytosed and
binds in a low pH milieu to FcRn, the immunoglobulin
is protected from lysosomal degradation. IVIg treatment may result in the saturation of FcRn receptors,
and through competition prevents pathogenic autoantibodies from binding, with the consequence of their
accelerated degradation. This hypothesis was supported
by a recent animal model, where, in FcRn knockout
mice, IVIg did not increase the clearance of a monoclonal anti-platelet anti-body, while in the wild-type animals it did.67,68
IVIg is capable of reversing the steroid resistant state.
Steroid resistance has been observed in asthma, SLE,
inflammatory bowel diseases, and transplant rejection.
In these patients, lymphocyte activation (thymidine
uptake in the presence of PHA) is not suppressed in the
presence of steroids. Five percent of the cases of steroid
resistance are genetic and 95% are acquired. In patients
unresponsive to glucocorticoids, a resistant isoform
(GR-␤) of the steroid receptor can be detected. IVIg
reverses steroid resistance state by reducing the binding
affinity of GR-␤ to glucocorticoids.69,70
New promising products have been designed and
introduced. Recently, anti-dsDNA idiotypes were
affinity purified from sera of SLE patients and were used
to isolate natural polyclonal anti-dsDNA anti-idiotypic
antibodies from IVIg preparations. These antibodies
improved the clinical manifestations of SLE in
(NZBxW)F1 mice in very low concentrations. The
lupus specific IVIg was introduced to a peptide phage
display library (C-7mer-C). The identified synthetic
peptides (idiotype mimetics) were synthesized and used
to replace the original human anti-dsDNA idiotype
column. Molecules affinity purified on the synthetic
peptide column from IVIg were determined as psIVIg
(peptide specific IVIg). These peptide-specific IVIgs
decreased the titer of circulating anti-dsDNA antibodies, and improved leucopenia, proteinuria, and immunoglobulin depositions in the kidneys, when injected
into mice with experimental SLE significantly greater
than conventional IVIg.71
It is possible that many of the discussed mechanisms
are not mutually exclusive and may contribute to the
success of IVIg therapy in different diseases. It has been
also suggested that some immunoregulatory effects of
IVIg are not due to the immunoglobulin fraction itself
but may be due to “contaminating” products present in
the product such, as growth factors.72It is very likely
that neither B cells, T cells, nor their cytokines are
required for the immediate/short-term protective effect
of IVIg. Our understanding of the mechanisms of IVIg
is expected to grow primarily regarding the medium
and long-term effects on the immune system. As we
discussed, IVIg affects both cytokines and cytokine
receptor levels. IL-2 is a key cytokine in the immune
response whose function is inhibited by IVIg. This inhibition appears to be upstream of IL-2 secretion, at a
posttranscriptional level.73 There are additional possible mechanisms for IVIg-induced changes in cellular
immunity. There is increasing understanding of the
immunological role of human regulatory T cells (Treg),
but the direct effect of IVIg on this cell population is
not known. While IVIg evidently inhibits T-cell proliferation and T cell cytokine production, it is not completely clear to what extent these effects are dependent
on the direct effects of IVIg on T cells or if they occur
mostly through the inhibition of antigen-presenting
cell activity including altered DC function. The study
of the IVIg mediated inhibitory signaling pathways on
specific cells, including T and B cells and monocytes, is
also an area where further explorations are needed.
IVIg Treatment in Organ Transplantation
Highly Sensitized Patients
The presence of antibodies of the IgG isotype, directed
against the HLA class I molecules presented by the
graft, correlates with episodes of severe acute rejections
and ultimate graft loss. These antibodies are demonstrated by “crossmatch”, when the serum of the recipient is incubated with lymphocytes from the donor, and
the potential binding exposed either through cytotoxicity with complement or through flow cytometry. The
positivity of a classical cytotoxic T cell IgG crossmatch
IVIg Treatment
was considered an absolute contra-indication for transplantation. A crossmatch positive by only flow cytometry does not rule out transplantation, but these patients
experience a significantly higher frequency of acute
rejections, with more severe lesions representing vasculitis. Reactivity of the actual serum sample obtained
from a patient on the waiting list is determined on a
panel of human cells representing the major HLA determinants. Highly sensitized patients, making up close to
30% of waiting lists, often have to wait prolonged periods for suitable organs and are at risk for early rejection
and/or graft failure.
Different IVIg preparations are used to treat prospective recipients who display high titers of donor specific anti-HLA antibodies. IVIg alone or in combination with plasmapheresis, anti-lymphocyte antibody, or
immunoadsorption techniques coupled with immunosuppressive agents effectively desensitizes these patients,
shortens waiting time, and facilitates transplantation74-77 as demonstrated by multiple studies in kidney
and heart transplantation. The mechanism may involve
a direct effect on circulating IgG anti-HLA immunoglobulins, as naturally occurring anti-idiotypic antibodies to HLA, which are also present in pooled human
IVIg, improve graft survival.30,78 IVIg has also been
demonstrated to stimulate the production of anti-idiotypic IgM blocking antibodies. Soluble HLA class I
molecules may transiently reduce anti-HLA activity by
binding to circulating anti-HLA antibodies in the
recipient.79,80 IVIg may also induce B cell apoptosis.81
The beneficial effect of pre-transplant IVIg treatment is further strengthened by a recent doubleblinded placebo-controlled multi-center study in kidney patients. The treatment consisted of IVIg 2 g/kg
monthly for 4 months or an equivalent volume of placebo. At baseline, the levels of panel reactive antibodies
(PRA) were similar. IVIg significantly reduced PRA
levels compared with placebo. The decrease in antiHLA antibody levels was sustained, and a significantly
higher percentage of patients could be transplanted in
the IVIg group (35 % vs. 17%). With a median follow-up of 2 years, the viable transplants functioned
normally, and the frequency adverse events rates was
similar.82
In addition to kidney and heart recipients, an ongoing study at our institution examines the use of IVIg in
highly sensitized patients awaiting small bowel transplantation. Isolated intestinal transplant (IIT) is preferable over multi-organ procedures for its typically better
outcome. A positive crossmatch in highly sensitized
patients on the intestinal waiting list is also considered
contraindication for IIT, as extensive graft damage or
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graft loss may develop due to humoral rejection.83 Several our patients have undergone desensitization using
various doses of IVIg (depending on the level of PRA).
A sustained reduction of PRA and, in some cases, negative crossmatch was achieved, and the patients were
successfully transplanted.84 This approach may facilitate earlier IIT in highly sensitized individuals who
would otherwise be offered multi-organ transplant after
they develop liver failure.
IVIg may also be administered at the time of transplantation for prevention of acute rejection. IVIgs have
been used for prophylaxis of acute rejection in hyperimmunized patients, including multi-organ procedures
performed in children as well as second transplants. In
hyperimmunized patients, post-transplant administration of IVIg (0.4 g/kg for the first 5 days after transplantation in addition to an immunosuppressive regimen
resulted in graft survival superior (95% at 2 years) to
typical results for this group of patients (approximately
80%).85 In a randomized study using IVIgs as prophylaxis for acute rejection, patients receiving 0.4 g/kg per
day from day 0 to day 5 with a quadruple immunosuppressive regimen had a significantly higher 5-year graft
survival rate (68%, vs. 50% in the control group).86 In
addition to these studies in kidney transplantation, a
similar study in heart transplant patients demonstrated
that the graft survival in immunized patients treated
with IVIgs and plasmapheresis was identical to the survival of non-immunized patients.87
IVIg preparations may also be useful in the treatment of established rejection, particularly when antilymphocyte antibody therapy is considered too risky. In
a study of 30 steroid-resistant rejections, IVIg treatment rescued over 70% of the grafts, without the wellknown side effects of OKT3.88 In addition to other
mechanisms described above, the beneficial effect of
IVIg in rejection may arise from neutralization of circulating anti-endothelial antibodies or by blocking
endothelial cell activation of the vascular lesions.89,90
IVIg is increasingly used to facilitate the transplantation of ABO incompatible organs such as kidney, lung,
and heart. Generally, IVIg is administered in combination
with immunosuppression, immunoadsoption, and plasmapheresis, and it is infused during the immediate pretransplant period.91,92 Successful treatment with IVIg of
antibody-mediated rejection following ABO-incompatible liver transplantation has also been reported.93
In liver transplantation, IVIg is an important therapeutic option in prevention of Hepatitis Bvirus (HBV)
recurrence. The introduction of high-dose HBIg for
long-term prophylaxis of HBV recurrence in patients
receiving transplants for HBV-related cirrhosis resulted
1476
Boros et al.
in survival rates comparable with those of liver transplants for other indications.94 While lamivudine is a
potential alternative to HBIg, lamivudine monotherapy has not proved satisfactory. As a combination
therapy, high doses of HBIg (5,000 IU) can be given
during the first 6 months post-transplant, followed by
lamivudine monotherapy. Recently, the use of low-dose
HBIg (2,000 IU) in association with lamivudine for
long-term maintenance has been recommended.95,96
Considering the high cost of HBIg treatment, other
groups suggests serial anti-HBs antibody titer determinations, which allows the identification of the optimal
timing for HBIg administration. This individualized
“on demand” approach appeared to be successful in
preventing recurrence over a 2-year period, and proved
to be cost-effective.97
IVIg and CMV infections in liver transplant
patients. Cytomegalovirus (CMV) infection emerged as
a serious problem for patients immunocompromised by
organ transplantation. Cytomegalovirus immunoglobulin (CIg) was licensed in 1991 and has regularly been
utilized to reduce CMV morbidity and mortality.
Treatment is expensive and does not always prevent
serious CMV disease. Several studies demonstrate that
CIg infusion reduces serious CMV infections associated
with liver transplants and improves survival of infected
patients.98,99 Reducing transplantation of organs from
CMV-positive donors to CMV-negative recipients
would be ideal but is usually not attainable. Recent
results demonstrate that adding prophylactic ganciclovir further reduces infection rates and improves survival
and clinical outcomes.100-103
Additional areas for IVIg treatment in liver transplant patients include idiopathic thromocytopenic purpura (ITP), which was reported following both cadaveric and living-related transplants.104,105 Successful
post-transplant treatment of chronic inflammatory
demyelinating polyradiculoneuropathy observed in
patients undergoing liver transplantation has also been
described.106
A recent addition to the indications for IVIg therapy
is post-transplant hypoglammaglubulinemia. This condition is being increasingly reported in liver, lung, and
heart transplant patients.107-109 The exact mechanism is
not clear, although heavy immunosuppression is likely
to play a role. Serious hypoglammaglubulinemia
(IgG ⬍ 350-400 mg/dL) is associated with increased
incidence of viral, fungal, and bacterial infections, in
certain cases an increased risk of rejection, and ultimately poorer outcomes. Pre-emptive treatment
appears to be beneficial, and the use of IVIg in post-
transplant hypogammaglobulinemia is viewed as an
accepted indication at several centers.110
Perspective
It is possible that many of the discussed mechanisms are
not mutually exclusive and may contribute to the success of IVIg therapy in different diseases. It has been also
suggested that some immunoregulatory effects of IVIg
are not due to the immunoglobulin fraction itself but
may be due to “contaminating” products present in the
product such, as growth factors. It is very likely that
neither B cells, T cells, nor their cytokines are required
for the immediate/short term protective effect of IVIg.
Our understanding of the mechanisms of IVIg is
expected to grow primarily regarding the medium and
long-term effects on the immune system. As we discussed, IVIg affects both cytokines and cytokine receptor levels. IL-2 is a key cytokine in the immune response
whose function is inhibited by IVIg. This inhibition
appears to be upstream of IL-2 secretion, at a posttranscriptional level. There are additional possible mechanisms for IVIg-induced changes in cellular immunity.
There is increasing understanding of the immunological role of human regulatory T cells (Treg), but the
direct effect of IVIg on this cell population is not
known. While IVIg evidently inhibits T cell proliferation and T cell cytokine production, it is not completely
clear to what extent these effects are dependent on the
direct effects of IVIg on T cells or if they occur mostly
through the inhibition of antigen-presenting cell activity including altered DC function. The study of the
IVIg mediated inhibitory signaling pathways on specific cells, including T and B cells and monocytes, is also
an area where further explorations are needed.
Although the exact mechanisms of action are not
fully understood, high-dose IVIg is an extremely valuable treatment option for a number of autoimmune
diseases as well as in patients with autoimmunity,
allergy, or special transplant-related problems who do
not respond to conventional therapies.
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