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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 95 No. 5 (March 1), 2000:
pp. 1856-1861
TRANSFUSIONMEDICINE
Vasoactive side effects of intravenous immunoglobulin preparations
in a rat model and their treatment with recombinant platelet-activating
factor acetylhydrolase
Wim K. Bleeker,
Jessica L. Teeling,
Arthur J. Verhoeven,
Gemma M. M. Rigter,
Jacques Agterberg,
Anton T. J. Tool,
Anky H. L. Koenderman,
Taco W. Kuijpers, and
C. Erik Hack
From CLB, Amsterdam, The Netherlands.
 |
Abstract |
Previously, we observed in a rat model that intravenous
administration of intramuscular immunoglobulin preparations induced a
long-lasting hypotension, which appeared to be associated with the
presence of IgG polymers and dimers in the preparations, but unrelated
to complement activation. We found evidence that this hypotensive
response is mediated by platelet-activating factor (PAF) produced by
macrophages. In this study, we compared the vasoactive effects of 16 intravenous immunoglobulin (IVIG) products from 10 different
manufacturers, in anesthetized rats. Eight of the IVIG preparations
showed no hypotensive effects (less than 15% decrease), whereas the
other 8 had relatively strong effects (15%-50% decrease). The
hypotensive effects correlated with the IgG dimer content of the
preparations. Pretreatment of the rats with recombinant PAF
acetylhydrolase completely prevented the hypotensive reaction on IVIG
infusion, and administration after the onset of hypotension resulted in
normalization of the blood pressure. We also observed PAF production on
in vitro incubation of human neutrophils with IVIG, which could be
blocked by anti-Fc receptor antibodies. This indicates that
induction of PAF generation may also occur in a human system. Our
findings support the hypothesis that the clinical side effects of IVIG
in patients may be caused by macrophage and neutrophil activation
through interaction of IgG dimers with Fc receptors. Because
phagocyte activation may also lead to the release of other inflammatory
mediators, recombinant PAF acetylhydrolase (rPAF-AH) provides a useful
tool to determine whether PAF plays a role in the clinical
side effects of IVIG. If so, rPAF-AH can be used for the treatment of
those adverse reactions.
(Blood. 2000;95:1856-1861)
© 2000 by The American Society of Hematology.
| |
Introduction |
Intravenous administration of immunoglobulin
preparations may cause anaphylactoid adverse reactions, including
headache, facial flushing, back pain, nausea, chills, fever, dyspnea,
hypotension, and circulatory shock. The incidence of these adverse
reactions is reported by the manufacturers to be in the range of 1% to
15%, usually below 5%.1,2 The reactions are generally
mild and self-limited and associated with a too high infusion rate.
Nevertheless, adverse reactions may pose a serious problem in the
treatment of some immunodeficient patients.
The side effects of immunoglobulin preparations are generally ascribed
to complement activation in the recipient by IgG aggregates in the
preparations. However, so-called intravenous immunoglobulin preparations (IVIG), which are made to be free of complement-activating activity in vitro, have been found to still cause clinical side effects, suggesting that other effector mechanisms are involved. Previously, we developed a rat model for the safety evaluation of
immunoglobulin preparations.3 We observed that standard immunoglobulin preparations (= Cohn Fraction II without additional treatment) induced a long-lasting hypotension that appeared to be
associated with the presence of IgG-polymers and dimers in the
preparations, but unrelated to complement activation. We found evidence
that this hypotensive response is mediated by platelet-activating factor (PAF) produced by macrophages.4 Others have
confirmed our findings5 and several investigators have
suggested the usefulness of the blood pressure response in animals for
predicting clinical tolerability of an IVIG product in
patients.6,7
In this study, we compared the hypotensive effects of 16 IVIG
preparations from different manufacturers in rats to see whether the
standard release criteria can guarantee the absence of vasoactive effects. Furthermore, we investigated the role of PAF in IVIG-induced hypotension by using a recombinant PAF acetylhydrolase
(rPAF-AH).8 Recombinant PAF-AH has the substrate
specificity and lipoprotein association of the native plasma PAF
acetylhydrolase and blocks PAF-mediated inflammatory reactions in vivo.
Therefore, we investigated whether rPAF-AH could provide a useful tool
to evaluate the role of PAF in clinical adverse reactions and whether
it might be used for their treatment.
| |
Materials and methods |
Animal model
Female Wistar rats (Harlan: HsdCpb:WU), weighing 180 to 250 g, were
anesthetized by intraperitoneal injection of pentobarbital, 60 mg/kg
body weight. Cannulas (Silastic®) were introduced into the right
jugular vein and left carotid artery. Saline was infused at a rate of 2 mL/h in each cannula to ensure patency. The arterial cannula was
connected to a pressure transducer for continuous recording of the mean
arterial blood pressure (MABP) and mean heart rate, both averaged over
10-second time intervals. Human IVIG preparations were given
intravenously in 10 seconds at a dose of 250 mg/kg, unless stated
otherwise. The test solutions were administered only if a stable MABP
(± 10 mm Hg) had been observed for a period of at least 10 minutes.
Each rat received only 1 dose of immunoglobulins. The whole procedure
took about 80 minutes, during which the rat remained anesthetized
without the requirement of additional pentobarbital. The experiments
were terminated 30 minutes after administration of the IgG test
solution by administration of a pentobarbital overdose.
Human neutrophil activation in vitro
Neutrophils were purified from peripheral human blood anticoagulated
with 0.4% (w/v) trisodium citrate, as described before.9 Briefly, mononuclear cells and platelets were removed by density gradient centrifugation over Percoll (density 1.077 g/mL).
Contaminating red blood cells were lysed by isotonic
NH4Cl/HCO3 treatment on ice. After isolation,
neutrophils were washed and resuspended in incubation medium
(4.106/mL), containing 132 mmol/L NaCl, 20 mmol/L HEPES, 6 mmol/L KCl, 1 mmol/L MgSO4, 1 mmol/L CaCl2, 1.2 mmol/L KPi, 5 mmol/L glucose, and 0.5% (w/v) human serum
albumin (pH 7.4). The neutrophils had a more than 95% purity.
Neutrophil activation was assessed at 37°C by mixing 1:1 with
prewarmed IVIG solutions (5 mg/mL). After 20 minutes of incubation, 0.8 mL samples (2.106 neutrophils/mL) were taken for the
measurement of the synthesis of PAF. PAF was measured with a
commercially available competitive radioimmunoassay (New England
Nuclear, Boston, MA) as previously described for
eosinophils.10 In short, the activation process of the
neutrophils was stopped by adding 3 mL methanol/chloroform 2:1 with 2%
(v/v) acetic acid added to the methanol. After separation of the
monophase with 1 mL chloroform and 1 mL H20, the lower
chloroform phase was stored at  70°C under nitrogen.
Subsequently, the chloroform phases were evaporated under a stream of
nitrogen and processed for the radioimmunoassay according to the
manufacturer's instructions. The amounts of PAF in the samples were
determined from a standard curve constructed with known amounts of PAF.
Recovery of PAF during the whole procedure was more than 90%.
In some incubations neutrophils were preincubated (10 mg/mL) with a
blocking monoclonal antibody (mAb IV.3) against Fc receptor (FcR)
type 2a.11,12
Immunoglobulin preparations
Sixteen human IVIG products were obtained from 10 different
manufacturers: Alpha Therapeutic Corporation (USA), Baxter Healthcare (USA), Biotest (Germany), BPL (UK), CLB (The Netherlands), FRC-BTS (Finland), Octapharma (Austria), Purissimus S.A. (Argentina), Sandoz
(Switzerland), and SSI (Denmark). Ten of the preparations were
licensed, whereas the others were still in a stage of preclinical or
clinical evaluation. All preparations complied with the release criteria of the European and US Pharmacopeia, in particular regarding anticomplementary activity, IgG-aggregate content, and prekallikrein activator activity. IgG dimer and polymer contents were determined by
size exclusion chromatography using a calibrated Superose 12 gel
filtration column in a FPLC system (Pharmacia, Uppsala, Sweden) and
computer analysis of the chromatograms (Ezchrom Chromatography Data
System). Table 1 gives the product codes
attributed to the preparations, the main characteristics of their
production process, and their formulation. Products B and E were
prepared at the CLB (The Netherlands). For all products IgG was
isolated from human pool plasma using cold ethanol fractionation, and
additional processing was applied to eliminate anticomplementary
activity and to improve clinical tolerability. Various additional
process steps were applied, including  -propiolactone treatment,
incubation at low pH with or without a small amount of pepsin,
diethylaminoethyl (DEAE) chromatography, PEG fractionation. The
preparations contained various stabilizers, including glucose, sucrose,
and albumin, and were freeze dried or liquid. Freeze-dried preparations
were administered within 2 hours after reconstitution, unless noted otherwise. A human IgG preparation for intramuscular administration (IMIG), essentially consisting of Cohn fraction II in a glycin buffer,
was obtained from the CLB (The Netherlands).
View this table:
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Table 1.
Overview of the different IVIG products tested: Main
steps in the production process intended to improve clinical
tolerability, the formulation, the percentage change in blood pressure
in rats, and the IgG dimer content of the tested lots
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One freeze-dried IVIG (product E) was stored in liquid state at 4°C
for more than 4 months after reconstitution to let occur IgG dimer
formation (IVIG-E aged). For control, the same product was frozen in
liquid nitrogen immediately after reconstitution and stored at
80°C (IVIG-E fresh). To dissociate the IgG dimers in IVIG-E
aged, the preparation was incubated at 37°C for 24 hours after
lowering the pH to 4.25 by dialysis against an acetate-containing formulation buffer. The preparation was then rapidly frozen and stored
at 80°C.
Recombinant PAF-AH, generously provided by Dr G. Dietsch (from ICOS,
Bothell, WA), was used as PAF antagonist. rPAF-AH was given
intravenously, as a bolus at a dose of 5 mg/kg, either 15 minutes
before, 5 minutes after, or 15 minutes after the immunoglobulin preparations.
Data analysis
Results are expressed as mean ± SD. Correlations between
variables were evaluated by calculating Spearman rank correlation coefficient using GraphPad Prism.
| |
Results |
Table 1 gives the changes in blood pressure 10 minutes after
administration of 16 different IVIG products, at a dose of 250 mg/kg in
10 seconds. Eight of these preparations induced no, or a minimal
hypotensive reaction (less than 15% decrease), whereas the other 8 products had a substantial hypotensive effect (15%-50%). For 8 products, 2 or more lots were tested, in all cases with similar
results. Hence, the effects on blood pressure were product-related rather than due to lot-to-lot variations. Figure
1 gives as an example the blood pressure
recordings after administration of either a product with minimal
hypotensive effect (IVIG-B) or a product with strong effect (IVIG-P).
The hypotensive reactions had the same time course as those previously
described for IMIG preparations3,4: the blood pressure
started to fall after 1 minute and reached a minimum level after 10 to
15 minutes. However, for all IVIG preparations, the hypotensive effects
were smaller than those induced by an IMIG preparation that was tested
for comparison (Table 1). By testing the IMIG preparation at different doses, the threshold bolus dose for hypotension (decrease in
MABP > 15%) was found to be between 10 and 30 mg/kg. To
investigate whether the rate of infusion was critical in this model,
IMIG was also administered by continuous infusion at a rate of 1 or 4 mg/kg/min. This way of administration also induced severe
hypotension, but the onset was delayed. The blood pressure started
to fall after an interval ranging from 5 to 20 minutes,
when a cumulative dose between 7 and 29 mg/kg was reached.
This indicated that the hypotensive effect was dose dependent
rather than rate dependent.
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| Fig 1.
Superimposed recordings of mean arterial blood pressure
(represented as percentage of baseline) of 3 rats receiving IVIG
product B (dotted lines) and 3 rats receiving IVIG product P (solid
lines).
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Figure 2 gives the relation between IgG
dimers and polymers in the preparations tested and the effects on the
blood pressure in rats. The IMIG preparation contained 18% dimers and
3% polymers. The changes in blood pressure correlated significantly
with the dimer contents (Spearman rank correlation
Rs = 0.4484, P = .016), but not with the
polymer contents (P = .20). It was remarkable that 1 IVIG
product (product-A, -propiolactone-treated) had a high dimer content
(2 lots: 12% and 14%), but did not induce hypotension.
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| Fig 2.
Relation between the changes in blood pressure in rats
(10 minutes after administration) and the IgG dimer ( ) and polymer
(x) contents of the IVIG preparations tested.
Each data point gives the mean percentage change in MABP of 3 experiments.
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|
The potency of rPAF-AH to prevent or treat of IVIG-induced vasoactive
reactions was investigated using IMIG as a model preparation for a
"bad" IVIG (Figure 3). Pretreatment
of rats with rPAF-AH (5 mg/kg) prevented the prolonged hypotensive
response, only a short-lasting transient decrease remained (Figure 3B).
Administration of rPAF-AH (5 mg/kg) 5 minutes after IMIG (250 mg/kg)
resulted in a complete reversal of the blood pressure (Figure 3C). This indicated that the hypotension was maintained by a sustained PAF release. However, administration of rPAF-AH 15 minutes after IMIG caused only partial restoration of the blood pressure (Figure 3D),
showing that also at this time point other mediators than PAF were
involved in the hypotension.
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| Fig 3.
Effect of rPAF-AH on IMIG-induced hypotension.
Saline, 15 minutes before IMIG, was used as control (A). rPAF-AH (5 mg/kg) was administered 15 minutes before (B), 5 minutes after (C) and
15 minutes after (D) IMIG (250 mg/kg). Each panel gives the
superimposed mean arterial blood pressure recordings of 3 rats.
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|
To further investigate whether the mechanisms of the hypotensive
reactions after IVIG and IMIG administration were the same, we followed
for several lots the change in molecular size distribution in
freeze-dried IVIG (product-E) after reconstitution and liquid storage
at 4°C. A gradual increase in dimer content was observed from less
than 5% to values above 10% after 1 week, which coincided with the
occurrence of hypotensive effects in rats. Figure
4A shows the chromatogram of IVIG-E that
was rapidly frozen after reconstitution and stored at 80°C
(IVIG-E fresh), and that of the same product, kept in solution at
4°C for 1 year after reconstitution (IVIG-E aged). The dimer
contents were 2.5% and 10%, respectively. The IgG dimers in IVIG-E
aged were dissociated by incubating the preparation for 24 hours at
37°C, pH 4.25 (Figure 4B: before and after pH 4). Figure
5 shows that dimer formation was
accompanied by the occurrence of a hypotensive effect (IVIG-E aged) and
that dissociation of the dimers by pH 4 treatment removed the
hypotensive effect. Pretreatment of rats with rPAF-AH prevented the
hypotension induced by IVIG-E aged and also that induced by another
IVIG product (IVIG-P).
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| Fig 4.
Size exclusion chromatograms of (A) an IVIG (product E,
see Table 1) that had been stored at 4°C for 1 year after
reconstitution of the freeze-dried product (IVIG-E aged), and that of
IVIG-E that was stored at 80°C immediately after reconstitution
(IVIG-E fresh) and (B) IVIG-E aged before (before pH 4) and after
incubation for 24 hours at 37°C, pH 4.25 (after pH 4).
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View larger version (38K):
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| Fig 5.
Changes in blood pressure (mean and SD, n = 3)
induced by IVIG-E fresh (see Figure 4A), IVIG-E aged (increased dimer
content, see Figure 4A), IVIG-E aged after pH 4 treatment (see Figure
4B) and by IVIG-P.
Furthermore, the effect of rPAF-AH pretreatment of the rats on the
hypotensive effect of IVIG-E and IVIG-P. The IVIG product codes
correspond to that in Table 1.
|
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All IVIG products tested in vitro, induced PAF synthesis in human
neutrophils, albeit to a different extent (Figure
6A). There was no obvious correlation
between the magnitude of the in vitro PAF synthesis and the in vivo
hypotension for the different IVIG preparations. However, in both
assays IMIG was the most potent activator. Preincubation of the
neutrophils with a blocking monoclonal antibody against FcR II (mAb
IV.3) largely prevented the IVIG-induced PAF production (Figure 6B).
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| Fig 6.
PAF production by human neutrophils in vitro after 20 minutes of incubation with IgG preparations.
The letters give the codes of the IVIG products as presented in Table
1. Panel B gives the effect of preincubation of the neutrophils with a
blocking anti-FcRII antibody (mAb IV.3). Results are the mean of
duplicate incubations.
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| |
Discussion |
Our study revealed major differences between different IVIG products
regarding their vasoactive properties in rats. About half of the
preparations tested had a pronounced hypotensive effect. All
preparations complied with the release criteria set by the European and
US Pharmacopoeia, in particular those regarding limits for IgG
aggregates and anticomplementary activity. These criteria came forth
from the idea that systemic complement activation by IgG aggregates in
the preparations is the major cause of clinical side effects in the
recipient. This was based on the observation of Barandun and
colleagues13 that immunoglobulin preparations could be
safely administered intravenously after elimination of the
anticomplementary activity. Therefore, manufacturers of IVIG have
implemented production steps to remove or inactivate IgG aggregates,
thereby eliminating the anticomplementary activity. However, our study
made clear that eliminating the complement-activating properties of
IVIG preparations does not necessarily eliminates all vasoactive
potential of IVIG. The most likely explanation seems to be that IgG
isolated from pooled plasma from numerous donors tends toward the
formation of dimers.14 The IgG dimers have no
anticomplementary activity but appeared to be almost as potent as IgG
polymers in inducing hypotension in rats.3 The storage
experiments with a reconstituted freeze-dried preparation, in which
vasoactivity was found to parallel the occurrence of dimers and
disappeared after their dissociation, confirm the role of dimers in
IVIG-induced hypotension. All IVIG products tested contained a certain
amount of IgG dimers, but vasoactivity seems to occur only when the
dimer content raises above a certain limit. A clear exception was
product D; the 2 batches tested had a relatively high dimer content
(12% and 15%), but showed no hypotensive effect. This suggests that
the chemical modification by -propiolactone treatment eliminates the
hypotensive effect by diminishing interaction with Fc receptors (see
below). This also raises the question whether this modification also
affects other Fc-effector functions of IgG in the preparation.
Previously, we found evidence that the IMIG-induced hypotension in rats
is mediated by PAF release from macrophages, independently from
complement activation.4 Therefore, we speculated that IgG
dimers in IVIG may activate macrophages through FcR triggering and
speculated that this is the major cause of clinical side effects of the
IVIG preparations currently available. This hypothesis finds support in
a recent clinical study in volunteers, comparing different experimental
IVIG preparations.15 In that study, a correlation was found
between IgG dimer content in the preparations and the occurrence of
clinical adverse reactions in humans and vasoactive effects in rats. In
addition, the clinical side effects in the humans were found to be
accompanied by a transient decrease in neutrophil and monocyte number
in the peripheral blood that paralleled an increase in TNFa serum
concentrations.15 Furthermore, we demonstrated the
possibility of FcR triggering by IVIG in a previous in vitro study,
in which we found that IgG dimers indeed bind to FcRII and FcRIII
on human neutrophils, and stimulate these cells via FcRII
triggering.16 This is consistent with the observation
in the in vitro part of this study that a monoclonal antibody
against FcRII could block the induction of PAF production by human
neutrophils. Taken together, these data point to a central role of the
activation of macrophages, monocytes, and possibly neutrophils in the
induction of clinical side effects.
In this study we evaluated the potential of rPAF-AH in treating
vasoactive effects of IVIG. A standard IMIG preparation, which is
basically Cohn fraction II dissolved in glycine-saline, was used as a
model for a "bad" IVIG preparation, in the sense that in the
early days of immunoglobulin therapy, side effects were frequently
observed on intravenous administration of these kind of preparations.
The experiments showed that pretreatment with rPAF-AH prevents
hypotension after IMIG infusion in rats. These results are consistent
with those of previous studies with PAF-receptor antagonists.4,5 Furthermore, administration of rPAF-AH
shortly after the start of the hypotension resulted in a complete
restoration of the blood pressure. This demonstrates that sustained PAF
release from macrophages (or other cell types) plays a central role in the induction and maintenance of hypotension after intravenous administration of immunoglobulin preparations to anesthetized rats. In
addition, we observed that IMIG and certain IVIG products induced PAF
production in isolated human neutrophils. We have no explanation for
the fact that there was no obvious correlation between the in vitro PAF
production and in vivo hypotension induced by the different IVIGs.
However, the in vitro results clearly demonstrated that activation of
phagocytes by human IVIG is not a particularity of rats but also occurs
in a human system. It also showed that PAF release results from direct
interaction of IVIG with phagocytes.
In a recent study in rats, we observed that IVIG preparations with high
IgG dimer content also induce activation of neutrophils in vivo
(Teeling et al, manuscript submitted). However, neutrophil activation
was not prevented by rPAF-AH pretreatment, showing that PAF plays no
major role in this effect and that rPAF-AH cannot prevent all effects
of FcR triggering by IVIG.
It has been stated that the standard, polyvalent IVIG products are
therapeutically equivalent and interchangeable.2 Our study,
however, shows that IVIG products may differ substantially regarding
their vasoactive side effects in rats, which points to differences in
the interaction with FcR. We expect therefore that the products
differ regarding the incidence of side effects.
In conclusion, our findings support the hypothesis that the clinical
side effects of the current IVIG product are caused by FcR
triggering on phagocytes by IgG dimers in the preparations. First,
we observed that many IVIG products induced hypotensive effects in
rats, which correlated with the dimer content of the product. Second,
rPAF-AH could effectively prevent these vasoactive effects indicating
that IVIG may induce significant PAF release in vivo and
suggesting that macrophage activation occurred. Finally, we observed
that IVIG may also induce PAF generation in a human system in
vitro. Because phagocyte activation may also lead to the
release of other inflammatory mediators, rPAF-AH provides a useful tool
to determine the role of PAF in the clinical side effects of IVIG in
humans. If PAF appears to play a role, rPAF-AH can be used for the
treatment of those adverse reactions.
| |
Footnotes |
Submitted August 2, 1999; accepted October 27, 1999.
Reprints: W. K. Bleeker, CLB, Dept PDH, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands; e-mail: w_bleeker{at}clb.nl.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
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Top
Abstract
Introduction