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TRANSFUSION MEDICINE
From the Department of Immunopathology, Central
Laboratory of the Blood Transfusion Service, Amsterdam, The
Netherlands.
Recently, it has been postulated that the beneficial effect of
intravenous immunoglobulins (IVIGs) in antibody-mediated autoimmune disorders is based on accelerated catabolism of autoantibodies. In the
current study, in vivo experiments were performed with mice in which
autoantibody production was mimicked by continuous infusion of
monoclonal antibodies. In this model, a single dose of IVIG reduced the
plasma concentrations of the infused immunoglobulin (Ig)G1 monoclonal
antibody (mAb) by approximately 40% after 3 days, whereas the
concentration of an IgA mAb was not affected. To extrapolate these
findings to humans, a computational model for IgG clearance was
established that accurately predicted the time course and magnitude of
the decrease in IgG plasma levels observed in mice. Adapted for humans,
this model predicted a gradually occurring decrease in autoantibody
levels after IVIG administration (2 g/kg), with a maximum reduction of
approximately 25% after 3 to 4 weeks and a continued decrease
of several months. In conclusion, a single high dose of IVIG induces a
relatively small but long-lasting reduction of autoantibody levels by
accelerated IgG clearance. This mechanism has clinical relevance in the
sense that it can fully explain, as the sole mechanism, the gradual
decrease in autoantibody levels observed in several patient studies.
However, in some clinical studies, larger or more rapid effects have
been observed that cannot be explained by accelerated clearance. Hence, IVIG can also reduce autoantibody levels through mechanisms such as
down-regulation of antibody production or neutralization by anti-idiotypic antibodies.
(Blood. 2001;98:3136-3142) Immunoglobulin preparations, originally developed
for the treatment of patients with agammaglobulinemia, have also been
successfully applied in a number of inflammatory and autoimmune
diseases, such as immune thrombocytopenic purpura, Kawasaki disease,
and Guillain-Barré syndrome. Several mechanisms of action of
intravenous immune globulin (IVIG) therapy in the latter disorders have
been proposed More than 30 years ago, it was found in several species that the
clearance rate of IgG greatly depends on its plasma
concentration.6 At low concentrations, the plasma
half-life is approximately 10 times longer than at high concentrations.
Brambell et al7 proposed in 1964 a hypothesis to
explain this phenomenon, stating that IgG is endocytosed in an
aspecific way. Part of this endocytosed IgG then binds to receptors in
the wall of the endocytotic vesicles to be protected from degradation
and is returned to the circulation (Figure
1). In this model, the protecting
receptors become saturated at high plasma concentration, resulting in
the degradation of a larger proportion of the endocytosed IgG.
Recently, experiments by several investigators with
The identification of FcRn as a protecting receptor has renewed
interest in the mechanism of IgG clearance and, as mentioned above, has
led to the hypothesis that the effect of high-dose IVIG in
autoantibody-mediated disorders is based on the saturation of FcRn,
leading to increased catabolism of IgG, including that of
autoantibodies.4,5 However, without knowing the
extent of reduction of autoantibody levels affected by this
mechanism, it is difficult to decide whether this mechanism has
any clinical significance in relation to the overall therapeutic
effects of IVIG therapy.
The aim of the current study was to determine the time course and the
magnitude of the decrease of autoantibody levels by IVIG therapy. This
was done first by studying the IVIG effect on immunoglobulin plasma
concentrations in a mouse model, in which autoantibody production was
simulated by a continuous infusion of monoclonal antibodies (mAbs).
Next, we established a computational model for IgG pharmacokinetics
using data from the literature on the concentration dependency of IgG
clearance in mice and humans. The model was validated by comparing
simulations with in vivo data from mouse experiments and was used to
predict the effects in humans. By comparing our results with those from
clinical studies, we concluded that accelerated clearance can explain
some, but not all, clinical observations on the reduction of
autoantibody levels.
In vivo clearance studies in mice
In the second series, we created a steady-state plasma level of
specific mouse IgG1 and IgA mAbs (without affinity for mouse antigens)
by continuous infusion and determined the effect of subsequent IVIG
administration on their plasma concentrations as described above.
Monoclonal antibodies were continuously infused using an osmotic pump
implanted in the peritoneal cavity (Alzet micro-osmotic pump, model
1002; Alza, Palo Alto, CA). Pumps with a pumping rate of 0.24 µL/h
for a duration of 14 days were filled with 100 µL mixture containing
0.3 mg/mL mouse IgG1 mAb to human C1 inhibitor and approximately 0.5 mg/mL mouse IgA mAb (in saline) to human interleukin-6 (IL-6). An
intravenous bolus dose of 35 µL infusate per mouse was given at the
beginning of infusion to obtain a steady-state plasma concentration
more quickly.
IVIG was intravenously administered at day 4 as a bolus dose of 1.8 g/kg body weight IgG. Animal experiments were approved by the local
ethics committee and were governed by the pertinent national legislation.
Immunoglobulin preparations
Assays for immunoglobulin (sub)classes and albumin in plasma Mouse IgG1, IgG2a, IgG3, and IgM plasma concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Capturing rat monoclonal antibodies to mouse IgG1, IgG2a, IgG3, or IgM (LO-MG1, LO-MG2a, LO-MG3, and LO-MM; Caltag, Burlingame, CA) were coated to 96-well Nunc Maxisorp plates (Nunc Brand Products, Roskilde, Denmark) by overnight incubation at room temperature at a concentration of 1 to 2 µg/mL in 0.1 M carbonate-bicarbonate, pH 9.6. Plates were washed twice in phosphate-buffered saline (PBS)-0.02% (wt/vol) Tween 20 (PBS-Tween). Plasma samples were appropriately diluted in PBS containing 2% (vol/vol) cow milk. One hundred microliters of each dilution was incubated for 1 hour at 4°C, and plates were gently shaken. Plates were washed 5 times in PBS-Tween and were incubated with biotinylated rat monoclonal anti-mouse light chain (226-BT; CLB)
as the detecting antibody, diluted 1:2000 in PBS containing 2%
(vol/vol) cow milk, for 1 hour at room temperature. Plates were then
washed 5 times in PBS-Tween and incubated with streptavidin-horseradish peroxidase (HRP; Amersham Life Science, Buckinghamshire, United Kingdom), diluted 1:1000 in PBS
containing 2% cow milk, for 30 minutes at room temperature. Finally,
the plates were developed with 3,3', 5,5'-tetramethylbenzidine (0.1 mg/mL in 0.11 M sodium acetate, pH 5.5, 0.003%
H2O2), and the reaction was stopped by the
addition of H2SO4. Absorbance was measured at
450 nm. Concentrations were expressed as percentages of those in normal
mouse serum (CLB).
Total mouse IgG concentrations in plasma were measured in a similar
ELISA with monoclonal anti-mouse Plasma concentrations of mouse IgG1 mAb to human C1 inhibitor (RII) was
measured in an ELISA with purified human C1 inhibitor (CLB) as the
capturing protein. Biotinylated rat mAb to mouse IgG1 (Caltag) was used
as conjugate; this was followed by incubation with
streptavidin-poly-HRP (CLB). Plasma concentrations of mouse IgA mAb to
human IL-6 (mAb 8- All above-mentioned ELISAs for mouse immunoglobulins were unaffected by
the presence of human IVIG in the samples, ruling out the presence of
anti-idiotypic antibodies to the RII and mAb 8- Computational model Figure 1B shows the 2-compartment pharmacokinetic model adopted for the simulation. The following assumptions were made: (1) produced and infused IgG are immediately mixed in the plasma compartment and redistributed by approximately 50% into the interstitial space11; (2) the plasma volume is 40 mL/kg body weight; (3) the exchange between the plasma and the interstitial pool is a linear process with rate constants (k1 = k2) of 0.087 for
mice and 0.014 for humans; and (4) the elimination of IgG occurs from
the plasma compartment according to a nonlinear process, with rate
constants depending on the plasma concentration. For mice, the relation between plasma IgG concentration and fractional clearance rate (FCR)
was derived from data published by several investigators who measured
the disappearance of tracer doses of radiolabeled IgG in mice with IgG
plasma concentrations ranging from 0.12 mg/mL to 50 mg/mL.12-15 Notably, these studies include experiments in germ-free and low-pathogen mice with low IgG plasma concentrations and
total body half-lives for IgG up to 9 days and in mice with plasma cell
tumors or receiving intraperitoneal injections of human IVIG and with
high IgG plasma concentrations and half-lives as brief as 1.5 days.
Figure 2 shows the sigmoid curve
fitted to the data points: FCRivp,
mouse = 0.055 + 0.79/{1 + e[(8.9  [IgG]pl)/5.9]}.
IgG plasma concentration ([IgG]pl) is expressed in milligrams per
milliliter mg/mL. FCRivp is the fraction of the
intravascular pool eliminated in 24 hours; it relates to the FCR of the
total body pool as FCRivP = FCRtbp/(fraction
of IgG intravascular). FCRtbP = ln2/t1/2, where
t1/2 is the total body half-life, or
elimination half-life, in days.
For humans, the relation between IgG plasma concentration and
FCRivp was derived from data published by Waldmann and
Strober,6 who reviewed several studies in humans with
widely varying IgG plasma concentrations, including patients with
hypogammaglobulinemia and myeloma, in whom IgG catabolism was
determined by measuring the disappearance of radiolabeled IgG from
plasma. Figure 2 shows the sigmoid curve fitted to the data points:
FCRivp,
human = Statistical analysis In vivo data are presented as mean ± SD. Results were compared with an unpaired or a paired Student t test, as indicated, using GraphPad Prism (GraphPad Software).
In vivo experiments in mice: effect of IVIG on endogenous immunoglobulin concentrations Administration of 1.8 g/kg IVIG to mice resulted in an increase of the total IgG plasma concentration (human plus mouse IgG) from approximately 3 to 33 mg/mL (Figure 3). Plasma concentrations of mouse IgG1 and IgG3 showed a gradual decrease to approximately 60% of baseline after 3 days (Figure 3). For IgG2a, the decrease was not significant because of a large standard deviation in the results. IgM and albumin concentrations showed a transient decrease after IVIG administration but returned to normal values after 3 days. Decreased albumin concentration indicated that transient plasma dilution occurred in the IVIG-treated mice, which could, at least partly, have accounted for the decreased IgG concentrations in the first 24 hours. This dilution effect was not significant in the control mice receiving saline, which has no oncotic effect. After 48 hours, albumin concentrations were back to baseline, indicating that the 40% decrease in endogenous IgG1 and IgG3 concentrations, 3 days after IVIG, was unrelated to dilution (Figure 3).
In vivo experiments in mice: effect of IVIG on plasma levels of infused monoclonal antibodies To obtain an experimental model that mimics production of autoantibodies in vivo, we continuously infused a mixture of IgG1 and IgA mAbs in mice by means of an implanted osmotic pump. We choose mAbs without affinity for mouse antigens to avoid binding to epitopes in vivo, which could make interpretation of the results difficult. An intravenous bolus dose (35 µL), followed by continuous infusion of the mAbs at a rate of 0.24 µL/hour, resulted after 3 days in steady-state plasma concentrations for IgG1 and IgA of 1.2% and 0.2%, respectively, of the concentration in the infusate. This difference in relative concentration is compatible with the difference in plasma half-life, which is reported to be much shorter for IgA.8 Figure 4 shows the effect of a single intravenous dose of 1.8 g/kg IVIG on the plasma levels of the mAbs, 4 days after the start of the infusion. The plasma concentration of the IgG1 mAb decreased by approximately 40%, whereas, as expected, the concentration of the simultaneously infused IgA mAb remained unchanged.
Control simulations To check whether the method of calculation was accurate, we first simulated for mice and humans the clearance of tracer doses of IgG at different endogenous IgG plasma concentrations (ranging from 1 to 60 mg/mL). Figure 5 shows the curves generated for humans. The t1/2 calculated from terminal parts of the double exponential curves ranged from approximately 50 days at an IgG concentration of 1 mg/mL to approximately 11 days at concentrations greater than 60 mg/mL, exactly as was expected from the relation between FCR and IgG plasma concentration used in this model.6 Furthermore, the intercepts of the terminal parts of the curves with the y-axis (time 0) were at plasma concentrations between 40% and 50% of the initial value after administration, indicating the expected redistribution of 50% to 60% of the dose into the interstitial space. For mice, the terminal parts of the double exponential curves (not shown) also showed the expected t1/2, ranging from 7 days at an IgG concentration of 1 mg/mL to 1.8 days at concentrations greater than 30 mg/mL.
Simulation of the IVIG effect in mice Figure 6 shows the simulated effect of intravenous administration of a single dose of IVIG on endogenous immunoglobulin concentrations in mice. In this simulation, the IgG production was set at 50 mg/kg per day, giving a basal IgG plasma concentration of 4.2 mg/mL, which is a normal concentration for laboratory mice.14 Administration of a single dose of 1.8 g/kg IVIG caused an increase in total IgG plasma concentration to 50 mg/mL, followed by a biphasic decline. The FCR increased more than 2-fold for several days, resulting in a gradual decrease in endogenous IgG concentration over several days and reaching a minimum after 3 to 4 days at approximately 65% of control, which corresponded well to the in vivo effects observed in mice (Figures 3, 4).
As expected, the magnitude of the effect of IVIG on endogenous IgG depended to some degree on the basal IgG concentration because at higher basal concentrations the FCR was already closer to the maximum value. For example, in simulations with a basal level of 1 mg/mL (production rate, 9 mg/kg per day), a dose of 1.8 g/kg induced a 40% decrease in endogenous IgG, whereas at 10 mg/mL (production rate, 190 mg/kg per day), the decrease was only 20%. Simulation of the IVIG effect in humans Figure 7 shows the simulated effect of intravenous administration of 2 g/kg IVIG to humans on IgG plasma concentration, FCR, and relative autoantibody levels. In this simulation, the values for k1, k2, and FCR are adapted for humans. Basal IgG production was set at 17 mg/kg per day, giving a basal IgG plasma concentration of 7 mg/mL. Autoantibody production is assumed to remain unchanged by IVIG administration. Administration of 2 daily doses of 1 g/kg IVIG (upper panel) caused a rise in plasma concentration to approximately 40 mg/mL, followed by a biphasic decline. FCR showed a sustained increase for several weeks, with initial doubling of the clearance rate. Autoantibody levels (endogenous IgG concentration) gradually decreased over several weeks, reaching a minimum after 3 to 4 days at approximately 75% of the pre-infusion level. The effect lasted more than 7 weeks. When IVIG was simulated to be given as 5 daily doses of 0.4 g/kg (lower panel), initial IgG concentrations were somewhat lower, but the magnitude of the effect on autoantibody levels was comparable.
In the in vivo experiments in mice, we first studied the effect of
IVIG administration on endogenous immunoglobulin concentrations. We
used human IVIG because it already had been observed by other investigators that human IgG has the same clearance characteristics in
mice as murine IgG.12,15 After a single high dose of IVIG, we observed a reduction of 40% in endogenous IgG1 and IgG3 levels that
occurred gradually and could not be ascribed to plasma
dilution after day 2. Only minimal changes were observed in mouse
IgG2a, which is in accordance with the findings of Israel et
al,9 who investigated subclass differences in the
concentration dependency of clearance. To better mimic the condition of
a patient producing autoantibodies, we next continuously infused mAbs
and investigated the effect of IVIG on their plasma levels. We
added an IgA mAb to the infusate as an internal control, because Ghetie
et al8 found that FcRn plays no protecting role in its
clearance. They also observed that IgA has a similar half-life in both
Simulations for mice accurately predicted the time course and magnitude of observed in vivo effects, both regarding the endogenous IgG (Figure 3) and the infused IgG1 mAb (Figure 4), which supported the validity of our computational model. It should be noted that in our in vivo experiments, plasma levels of endogenously produced IgG were reduced to the same extent as IgG1 mAb infused at a fixed rate. This supports the idea that there is no immunoregulatory feedback on IgG synthesis,16 and it justifies the assumption in our pharmacokinetic model that IgG production is constant for a patient, independent of IgG concentration. A conspicuous finding was the extended time course of the IgG reduction after a single dose of IVIG. Further analysis of our model revealed that the critical element in this respect is the FCR-concentration relation, which was based on data from the literature.6,12-15 Other elements, such as the rate of equilibration between plasma and interstitial pool, had only a minor influence on the simulated effects. The slow kinetics of the effect prevents steady-state conditions from being reached after a single IVIG dose and may explain why the effect is smaller than might be intuitively expected. Because IgG autoantibodies are expected to have the same clearance behavior as all other plasma IgG, our simulations also predict the effect of IVIG on the level of freely circulating IgG autoantibodies. We do not want to speculate about whether a 25% decrease in autoantibody level could have pathophysiological significance and will limit the discussion to whether the mechanism of accelerated clearance can explain the IVIG-induced reduction in autoantibody titers observed in clinical patients. We compared the predictions from our simulation with clinical data from patient studies. Bain et al17 performed a randomized, placebo-controlled crossover trial on IVIG therapy in 9 patients with Lambert-Eaton myasthenic syndrome. The patients received IVIG on 2 consecutive days at a dose of 1 g/kg body weight per day or an equivalent volume of 0.3% albumin. They measured calcium-channel antibodies using an immunoprecipitation assay. Their observations closely corresponded to the effects predicted by our model (Figure 7): after IVIG infusion, total IgG plasma concentrations increased from 7 to approximately 40 g/L and gradually decreased toward normal values over a period of more than 6 weeks. During this period, autoantibody levels gradually decreased by approximately 30% after 3 weeks, remaining below pre-infusion levels for at least 8 weeks. No changes were observed after albumin administration. Notably, in vitro, using the same immunoassay, the investigators found no evidence for anti-idiotype autoantibody neutralization by IVIG, ruling out the possibility that the lower autoantibody levels were caused by neutralization of antibody activity by IVIG. Hence, in these patients, the IVIG-induced decrease in autoantibody titers can be fully explained by accelerated IgG clearance as the sole mechanism. Similar reductions in autoantibody levels have been described by Jayne et al18 after high-dose IVIG treatment of 8 patients with systemic vasculitis. They observed a gradual reduction in antineutrophil cytoplasm autoantibodies (ANCA) by approximately 30% after 5 weeks that lasted for at least 10 weeks. These authors suggest that this reduction is caused by the suppression of ANCA production by ANCA anti-idiotype antibodies in IVIG. However, our simulation reveals that a reduction of this magnitude can entirely be explained by enhanced catabolism. Because the effects on autoantibody levels in the above-mentioned studies are completely covered by the effect of an accelerated clearance as predicted by our model, the question arises whether other proposed mechanisms of IVIG therapy may also play a role in decreasing autoantibody levels in patients. On the one hand, some observations suggest that this may not be the case; on the other hand, findings from several clinical reports on large and rapid changes in autoantibody levels cannot be explained by accelerated clearance. For example, assuming other mechanisms of reduction in antibody levels, such as neutralization by anti-idiotypes or down-regulation of production, one should expect that IgM autoantibodies would also be reduced by IVIG therapy. Yet, Hammerström et al19 used an autoimmunity model based on SCID mice reconstituted with peripheral blood lymphocytes from a patient with primary biliary cirrhosis, which is associated with anti-M2 autoantibodies. In this model, they observed that mice treated with repeated dosages of IVIG after reconstitution showed markedly lower anti-M2 IgG plasma levels, whereas anti-M2 IgM levels were not influenced. Consistent with this, Dalakas et al20 observed, in a selected series of 11 patients with demyelinating polyneuropathy associated with monoclonal IgM antibodies against myelin-associated glycoprotein and sphingoglycolipids, neither an appreciable change in antibody titers nor a clear clinical benefit after IVIG therapy. In contrast to the studies discussed above, several clinical
observations on rapid reductions in antibody levels favor a role for
other mechanisms. Levy et al21 studied the effect of IVIG on autoantibody levels before and after 5-day treatment courses in 3 patients with systemic vasculitis. Unlike an earlier study by Jayne et
al,18 they observed erratic changes in
anti-myeloperoxidase and anti-PR3 levels (5-fold increases or
decreases or no change at all in 2-week intervals). Sultan et
al22 observed, in 2 patients with hemophilia, a more than
10-fold reduction in anti-VIIIc activity within 5 days of IVIG therapy.
Because IVIG also inhibited anti-VIIIc activity in patient plasma in
vitro, they found evidence that the effect of IVIG was based on the
presence of anti-idiotypic antibodies. In a prospective study on IVIG
treatment of acquired factor VIII autoantibodies, Schwartz et
al23 measured inhibitor titers in 8 of 16 assessable
patients. In 6 patients the inhibitor completely disappeared after IVIG
therapy, and in 3 of them a strong decline already occurred within 4 days. It should be noted that in these studies, factor VIII inhibitor
levels were measured using a functional assay (Bethesda units); the
results are difficult to translate into free antibody concentrations.
Nevertheless, the observed changes seem to be too rapid and too large
to be explained by accelerated clearance, which strongly suggests that IVIG may also reduce antibody levels by other mechanisms. A rapid decrease in autoantibodies is compatible with direct neutralization through binding to anti-idiotypic antibodies in IVIG, after which they
will escape detection in an assay. Gradually occurring, long-lasting, complete disappearance may point to a down-regulation of antibody production, such as, for example, an effect on B cells that could possibly be affected by Fas-mediated induction of
apoptosis,24 interaction of anti-idiotypic antibodies in
IVIG with inhibitory Fc In summary, our study shows that IVIG therapy induces a relatively long-lasting, but modest, reduction of autoantibody levels by accelerated IgG clearance. This mechanism has clinical relevance in the sense that it can explain, as the sole mechanism, the gradual 20% to 40% decrease in autoantibody levels observed in several patient studies. However, larger or more rapid effects observed in some other clinical studies cannot be explained by accelerated clearance, suggesting that IVIG can also reduce autoantibody levels through other mechanisms.
We thank Mr Theo Jansen-Hendriks for excellent technical assistance.
Submitted April 24, 2001; accepted July 17, 2001.
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.
Reprints: Wim K. Bleeker, Department of Immunopathology, Central Laboratory of the Blood Transfusion Service, Dept PDH, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands; e-mail: e_hack{at}clb.nl.
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© 2001 by The American Society of Hematology.
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Top
Abstract
Introduction
blocking of Fc receptors on phagocytes, inhibition of
complement deposition, modulation of cytokine production,
neutralization of circulating autoantibodies by anti-idiotypic
antibodies, and down-regulation of autoantibody production by
anti-idiotypic antibodies interacting with B cells.
2-microglobulin
knock-out mice provided solid support for the existence of such a
protecting receptor.
) was purified from culture
supernatant using size exclusion chromatography to isolate monomeric
IgA. Both monoclonal antibodies have been characterized and produced in
our department.
RIIb-receptor,