modulating effects of intravenous immunoglobulins on serum cytokine levels in patients with primary...

Biodrugs 2005; 19 (1): 59-65ORIGINAL RESEARCH ARTICLE 1173-8804/05/0001-0059/$34.95/0

© 2005 Adis Data Information BV. All rights reserved.

Modulating Effects of IntravenousImmunoglobulins on Serum Cytokine Levels inPatients with Primary HypogammaglobulinemiaCristina Ibanez,1 Pilar Sune,1 Ana Fierro,1 Santiago Rodriguez,2 Maite Lopez,3 Antonio Alvarez,4 Javier DeGracia4 and Jose-Bruno Montoro1

1 Department of Pharmacy, Hospital Vall d’Hebron, Barcelona, Spain2 Department of Biochemistry, Hospital Vall d’Hebron, Barcelona, Spain3 Grifols Laboratories, Barcelona, Spain4 Department of Pneumology, Hospital Vall d’Hebron, Barcelona, Spain

Background: Intravenous immunoglobulins (IVIG) have usually been administered for replacement therapy ofAbstracthumoral immunodeficiencies, but their use in treating other disorders with an immune pathogenesis isincreasing. The exact mechanism of action by which IVIG are of benefit in such diseases is complex and onlypartly understood. One of the proposed mechanisms of action is the modulation of cytokine release.Methods: We selected 29 patients with primary hypogammaglobulinemia (common variable immu-nodeficiency), receiving long-term substitutive therapy with IVIG, and 14 healthy blood donors as a controlgroup. Blood samples were then taken before and 1 hour after finishing the IVIG infusion. Only one bloodsample was obtained from the healthy controls. The cytokines studied were interleukin (IL)-1β, IL-1 receptorantagonist (IL-1Ra), IL-2, IL-6, IL-8, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ.Results: Patients with primary hypogammaglobulinemia showed significantly higher serum levels of IL-6, IL-8,IL-1Ra, and TNFα than healthy controls. IVIG infusion significantly increased serum concentration levels ofIL-6, IL-8, IL-1Ra, and TNFα. No significant variation was observed in serum levels of IL-β, IFNγ, or IL-2 afterIVIG infusion. Age, IVIG commercial preparation, and IVIG dose did not influence cytokine serum levels.Moreover, a significant correlation was observed between serum level variations of IL-1Ra and TNFα, as well asan associative trend between maximum changes in IL-6 and IL-8 concentrations.Conclusions: IVIG administration significantly alters the serum pattern of selected cytokines, which mightexplain, at least in part, the mechanism of action of IVIG in autoimmune or inflammatory disorders.

Immunoglobulin preparations for intravenous use (IVIG) have The mode of action of IVIG is complex and the exact mecha-been successfully used since the 1960s to treat a variety of symp- nism of action explaining the therapeutic benefit of IVIG is onlytoms and conditions related to disorders of the immune system. partly understood. Beyond the administration of larger quantitiesIVIG were initially administered for the replacement therapy of of passive antibodies, several complementary mechanisms of ac-primary and secondary humoral immunodeficiencies,[1] but their

tion have been proposed. These include Fc receptor blockade;use is currently increasing to other disorders with an immune

inhibition of complement activation; down-regulation of B- and T-pathogenesis, such as thrombocytopenias,[2] inflammatory neuro-

cell function; neutralization of super-antigens, bacterial toxins, orlogic diseases,[3] Kawasaki disease,[4] atopic dermatitis,[5] ster-immuno-activating cytokines; idiotype-anti-idiotype interactions;oid-dependent asthma,[6] and prevention of graft-versus-host dis-modulation of cytokine production; and enhancement of the clear-ease.[7] The benefit of IVIG in other diseases is clear, although not

fully understood. ance rate of endogenous pathogenic autoantibodies.[2,8-13]

60 Ibanez et al.

Growing evidence indicates that IVIG modulate cytokine pro- ered strictly under empirical grounds. Thus, IVIG administrationduction in vitro.[8-10] The effect of IVIG administration in vivo has schedules are not clearly defined, early surrogated efficacy mark-been studied less frequently, since IVIG administration to healthy ers do not exist, and patient clinical condition is the only key tovolunteers cannot be considered on ethical grounds, and the regulating IVIG administration. Furthermore, it is not clear wheth-clinical conditions of autoimmune disease patients often masks the er or not the different IVIG commercial preparations are therapeu-true effects of IVIG products, in terms of surrogate markers such tically equivalent, since the labeled indications are distinct foras serum cytokines. each preparation.

On the other hand, the fact that no clear mechanism of action Therefore, the aim of this study was to investigate how IVIGhas been established for IVIG means that IVIG therapy is consid- administration influences serum levels of different cytokines in

patients with primary hypogammaglobulinemia (common variableimmunodeficiency), to better understand the IVIG mechanism ofaction.

Materials and Methods

Study Population

Twenty-nine patients (13 men and 16 women; mean age 52years; range 21–80 years) with documented diagnosis of primaryhypogammaglobulinemia (common variable immunodeficiency)were included in the study (patient characteristics are shown intable I). All patients followed long-term substitutive therapy withIVIG at the outpatient setting of our center (Vall d’Hebron Hospi-tal, Barcelona, Spain). Patients with acute infection or undergoingantibacterial treatment, and patients with a clinically detectableinflammatory status were excluded from the study. Fourteenhealthy blood donors were also selected as the control group.

Institutional Review Board (Ethics Committee) permission wasreceived and informed consent was obtained from each patientbefore entering the study.

Immunoglobulin Preparation

IVIG preparations used in the study were those present in theSpanish market, either in liquid presentation: Flebogamma® 1

(Instituto Grifols, Barcelona, Spain) or in lyophilized powder:Endobulin S/D® (Baxter SAE, Madrid, Spain) or Gammagard S/D® (Baxter SAE, Madrid, Spain).

Immunoglobulin Administration Regimen

The patients included in this study received a mean dosage of330 mg/kg of IVIG (range 160–600 mg/kg) every 21 or 28 days.The IVIG dosages administered varied widely, ranging between10g and 30g (mean 20.5g).

Table I. Patient characteristics and intravenous immunoglobin (IVIG) ad-ministration regimen. All patients were diagnosed with common variableimmunodeficiency

Patient Age [y] IVIG preparation IVIG dosage [g (mg/kg)] and(sex) administration interval

1 42 (F) Flebogamma® 15 (290) every 21 days

2 22 (M) Flebogamma® 25 (380) every 28 days


4 60 (M) Endobulin® 20 (350) every 21 days




8 48 (F) Endobulin® 25 (620) every 21 days












20 45 (F) Gammagard® 20 (260) every 28 days




24 58 (F) Gammagard® 20 (400) every 21 days






F = female, M = male.

1 The use of trade names is for product identification purposes only and does not imply endorsement.

© 2005 Adis Data Information BV. All rights reserved. Biodrugs 2005; 19 (1)

Immunoglobulins and Cytokine Serum Levels 61

Study Design Statistical Analysis

The patients received their periodic IVIG administration at the Statistical analysis was performed using a commercially availa-outpatient setting of our center, in accordance with each manufac- ble computer program (SPSS, version 8.0, Statistical Consultantsturer’s instructions. Blood samples were taken before and 1 hour Inc., Chicago, IL, USA). The distribution of all quantitative vari-after finishing the infusion. For healthy controls, only one blood ables was examined to detect significant departures from normali-sample was obtained. ty by means of the Shapiro-Wilks test. However, for descriptive

The cytokines studied were interleukin (IL)-1β, IL-1 receptor purposes, mean and standard deviation were used independently ofantagonist (IL-1Ra), IL-2, IL-6, IL-8, tumor necrosis factor the type of distribution. Values for cytokines among treatment(TNF)-α, and interferon (IFN)-γ. groups were compared using the Student’s t-test (Mann-Whitney

U-test, when necessary). Changes in serum levels of cytokines,Blood Sampling Protocol before and after IVIG administration, were compared using t-test

for paired samples (Wilcoxon matched paired test, when necessa-Blood samples were drawn into sterile pyrogen-free vacuum

ry). Lineal regression/correlation was used to assess associationsblood collection tubes using sodium heparin (15 U/mL) as antico-

among cytokines. The association with categoric variables wasagulant. Tubes were immediately immersed in melting ice and

evaluated by an analysis of variance (ANOVA). p-Values are twocentrifuged within 20 min (400g and 4ºC for 10 minutes). After the

sided and considered significant when p < 0.05.first centrifugation, serum was then transferred to sterile Ep-pendorf tubes and further centrifuged (10 000g and 4ºC for 5

Resultsminutes) to obtain platelet-free serum. Serum was stored at –70ºCin multiple aliquots until analysis was run. Samples were frozenand thawed only once. To minimize run-to-run variability, all

Serum Levels of Cytokines in Patients withsamples were analyzed in duplicate and at the same time (on thePrimary Hypogammaglobulinemiasame microtiter enzyme immunoassay [EIA] plate).

Serum cytokine levels were characterized at baseline (beforeEnzyme ImmunoassaysIVIG infusion) in patients with primary hypogammaglobulinemia

For the quantification of IL-1β, IL-1Ra, IL-2, IL-6, IL-8, and in healthy control individuals. Patients with primary hy-TNFα, and IFNγ, commercially available ELISA kits were used pogammaglobulinemia had significantly raised serum levels of(Biosource International Inc., CA, USA). Processing of samples IL-6, IL-8, IL-1Ra, and TNFα, whereas the levels of the remainingwas performed following manufacturer’s instructions. In all cases, cytokines (IL-1β, IL-2, and IFNγ) were not statistically different insamples were analyzed in duplicate. the two groups (table II).

Table II. Variation of cytokine levels between healthy controls and patients with primary hypogammaglobulinemia

Cytokine Healthy controlsa,b Before IVIG infusiona,c p-Valued After IVIG infusiona,c p-Valuee

IL-1β (pg/mL) 1.103 (0.541) 1.346 (0.696) 0.697 0.673 (0.482) 0.262

IL-2 (U/mL) 0.438 (0.081) 0.405 (0.019) 0.736 0.417 (0.043) 0.939

IL-6 (pg/mL) 3.053 (1.971) 10.307 (10.576) 0.002 30.587 (37.265) 0.008

IL-8 (pg/mL) 0.446 (0.556) 0.748 (0.722) 0.038 2.693 (4.016) 0.032

IL-1Ra (pg/mL) 55.640 (22.67) 83.490 (40.66) 0.020 132.830 (83.72) 0.037

TNFα (pg/mL) 21.160 (5.19) 33.470 (17.12) 0.002 51.860 (28.08) <0.001

IFNγ (pg/mL) 3.100 (4.356) 6.135 (5.271) 0.430 11.880 (8.99) 0.134

a Data are given as mean (standard deviation).

b Only one sample was obtained from healthy controls.

c In the patients group, blood samples were taken just before and 1 hour after IVIG infusion.

d Statistical significance between cytokine levels of healthy controls and patients before IVIG infusion.

e Statistical significance between cytokine levels of patients before and after IVIG infusion.

IFN = interferon; IL = interleukin; IVIG = intravenous immunoglobin; Ra = receptor antagonist; TNF = tumor necrosis factor.


62 Ibanez et al.

Associations Between Cytokine Serum Variations andOther Variables

No association was found between age, dosage, or IVIG com-mercial preparation and changes in serum levels of thesecytokines. Unexpectedly, a significant positive association be-tween the changes in serum levels of IL-1Ra and a demographiccharacteristic, the female sex, was found (mean increase in malepatients: 13.28; mean increase in female patients: 65.82; p =0.033).

Discussion

This study is one of the few works in vivo that demonstrates thatIVIG administration modulates the complex cytokine network.When analyzing and comparing the results available in the litera-ture (table IV), some conflicting observations are reported, whichmight be explained by the different methodologies employed byeach study group. It is also very difficult to extrapolate data fromin vitro models to the in vivo situation, since the immune system isthe outcome of a complex network where different componentsand processes interact in vivo, and there are questions that remainunanswered with this regard. Furthermore, in vitro studies are

0

20

40

60

80

100

120a

IL-6

(pg

/mL)

0

1

2

3

4

5

6b

IL-8

(pg

/mL)

0

50

100

150

200

250

300c

IL-1

Ra

(pg/

mL)

0

50

100

150

200

d

TN

F-α

(pg

/mL)

Pre-infusion Post-infusion Pre-infusion Post-infusion

Fig. 1. Serum levels of the cytokines varying significantly after intravenousimmunoglobulin infusion in patients with primary hypogammaglobulinemia:(a) Interleukin (IL)-6, (b) IL-8, (c) IL-1 receptor antagonist (Ra), and (d)tumor necrosis factor (TNF)-α. Data are given for each individual patient.

usually obtained with the stimulation of monocytes/macrophagesIn Vivo Effect of Intravenous Immunoglobin (IVIG) Infusion from a healthy population, which would behave differently from

patients with an immunologic disease.on Serum Cytokine Levels

Our study was performed with patients with primary hypogam-maglobulinemia (common variable immunodeficiency), which, asAs shown in table II, IVIG infusion significantly influenceddemonstrated, had different baseline cytokine levels from those ofserum levels of IL-6, IL-8, IL-1Ra, and TNFα, in terms of increas-healthy controls. These results are consistent with previous stud-ing their concentrations. Nevertheless, there were four patientsies, where Aukrust et al.[20] showed a state of chronic immune

who responded somewhat differently. Two patients had a fall inactivation, with elevated serum levels of different cytokines, in

serum levels of IL-6 and IL-8, and one patient had, in addition topatients with this disorder. Recurrent bacterial infections are the

these cytokines, decreased levels of IL-1Ra. Finally, there was one most common clinical manifestations in patients with primarypatient in which IL-8 and TNFα levels were reduced following hypogammaglobulinemia, but inflammatory conditions, autoim-IVIG infusion (figure 1). mune disease, or lymphoproliferative syndromes may also be

observed.[21] Some alterations that could explain these featuresNo significant variation was found in serum levels of IL-β,

IFNγ, or IL-2 after IVIG infusion (table II).

Correlations Between Changes in Serum Levels of

Different Cytokines After IVIG Infusion

When analyzing the correlations between those cytokines that

varied significantly after IVIG infusion (table III), the maximum

changes in serum level of IL-1Ra were strongly positively corre-

lated with the maximum changes in serum level of TNFα. Further-

more, an associative trend between maximum changes in IL-6 and

IL-8 concentrations was observed.

Table III. Correlations (r) between maximum changes in serum levels ofthose cytokines that varied significantly after intravenous immunoglobininfusion

Cytokine IL-6 IL-8 IL-1Ra TNFα

IL-6

IL-8 0.532a

IL-1Ra 0.285 0.135

TNFα 0.277 0.199 0.569b

a p < 0.1.

b p < 0.01.

IL = interleukin; Ra = receptor antagonist; TNF = tumor necrosis factor.



Table IV. Cytokine modulation by intravenous immunoglobin observed in previous studies carried out in vitro and in vivo

Cytokine Effect in vitro Cell type Effect in vivo Patient population

IL-1α Unaffected Monocytes[8,10] Down-modulation Primary hypogammaglobulinemia[14,15]

IL-1β Unaffected Monocytes[8,10] Down-modulation Primary hypogammaglobulinemia,[14,15]

Guillain-Barre Syndrome[16]

IL-1Ra Up-modulation Monocytes[8] Up-modulation Primary hypogammaglobulinemia[14,15]

IL-2 Down-modulation T cells[8,10] Unaffected Second generalized epilepsy[17]

IL-2R Down-modulation T cells[10]

IL-6 Down-modulation Monocytes[8,10,18] Up-modulation Primary hypogammaglobulinemia,[14]

second generalized epilepsy [17]

Down-modulation Kawasaki disease[18]

IL-8 Up-modulation Monocytes[8] Up-modulation Primary hypogammaglobulinemia[14]

Unaffected T cells[10]

Down-modulation T cells[18]

IL-10 Down-modulation T cells[8,10] Up-modulation Immune thrombocytopenic purpura[19]

TNFα Unaffected Monocytes, T cells[8,10] Up-modulation Primary hypogammaglobulinemia[14]

Down-modulation T cells[9,18] Down-modulation Guillain-Barre Syndrome[16]

TNFβ Down-modulation T cells[10]

IFNγ Down-modulation T cells[8,9] Up-modulation Second generalized epilepsy[17]

Unaffected T cells[10]

IFN = interferon; IL = interleukin; R = receptor; Ra = receptor antagonist; TNF = tumor necrosis factor.

have been identified, such as defects in the memory B-cell pool explained by different study methodologies, as previously dis-and deficient immunoglobulin secretion, as well as T-cell function cussed. Following an in vitro model of allograft rejection,abnormalities leading to diminished proliferative responses to Toungouz et al.[9] showed that IVIG could block lymphocyteantigens or alterations in the production of several cytokines.[21] proliferation and TNFα production, leading to a beneficial immu-The main mechanism influencing clinical manifestations of prima- nosuppressive effect when IVIG are used after bone marrowry hypogammaglobulinemia remains unclear. transplantation. Nonetheless, Aukrust et al.[14] observed that TNFα

levels were significantly increased after IVIG administration inA considerable increase in IL-1Ra release has been observed,vivo, although they returned to baseline values some hours later,but no statistically significant variation in IL-1β levels was ob-because of IVIG-induced release of soluble TNFα receptors. Sincetained. Data from previous reports indicate that IVIG administra-the presence of such neutralizing soluble receptors was not stud-tion in vivo modulates several components of the IL-1 system.[14,15]

ied, it cannot be excluded and it is feasible that TNFα levels couldIVIG could down-regulate IL-1 synthesis by monocytes/macro-later be reduced.phages, as well as up-regulate neutralizing antibodies against IL-1.

Moreover, IVIG are potent inducers of IL-1Ra release, the natural There are also discrepancies in reports of IL-6 modulation byantagonist of IL-1 with anti-inflammatory properties. The suppres- IVIG. While experiments with peripheral blood mononuclear cellssion of this cytokine may be of interest, since IL-1 seems to be show a suppressive effect of IVIG upon IL-6 production,[10] otherinvolved in the pathogenesis of a wide range of immune-mediated studies carried out in vivo[14,17] report an increase in serum levels ofdisorders, such as Kawasaki disease or Guillain-Barre syn- IL-6. Biologic functions of IL-6 are somewhat similar to IL-1 anddrome.[16,22] As it has been previously stated,[14] dimer pairs and TNFα and it is required for the differentiation of B-cells intoimmune complexes present in IVIG obtained from pooled serum immunoglobulin-producing serum cells. However, IL-6 hascould stimulate IL-1Ra release and other cytokines, such as TNFα, shown anti-inflammatory properties, since it could suppress lipo-IL-6, IL-8, and IFNγ. An increase in serum levels of all these polysaccharide (LPS)-induced TNFα and IL-1 release.[23]

cytokines was observed in our study, but IFNγ did not show a Even though there was a slight increase in circulating IFNγstatistically significant increase. serum levels, this did not reach statistical significance compared

When reviewing data from the literature, conflicting observa- with baseline values. Nevertherless, previous studies in vivo showtions regarding TNFα modulation by IVIG are found. This may be that IVIG induce IFNγ release.[14,17] It has also been reported that


64 Ibanez et al.

IVIG down-regulate IL-2 production and IL-2 receptor expres- on other criteria. Similarly, the wide range of dosages employedsion.[10] However, no significant variations in serum levels of IL-2 showed no association with the variation of cytokines. It is feasiblewere observed in the present study. that lower dosages of IVIG could produce similar effects in the

cytokine network, thus likely reducing adverse reactions and eco-A strong positive correlation between the maximum change innomic costs, definitively optimizing pharmacotherapy. This hy-IL-1Ra concentration and the maximum change in TNFα levelpothesis needs further investigation, since the aim of IVIG treat-was found in this study. This correlation could be explainedment in patients with primary hypogammaglobulinemia, autoim-because both cytokines are monocyte/macrophage derived, and itmune, or inflammatory diseases is different.has been suggested that TNFα induces IL-1Ra production in a

promyelocytic cell line, as a mechanism of back-regulation of theConclusionsinflammatory activity of TNFα.[24] A positive associative trend

between maximum changes of the serum levels of both IL-6 andThe results of this study indicate that IVIG administration has aIL-8 was also observed, in accordance with other studies carried

modulating effect in vivo on the circulating cytokine network,out in vivo.[14,25]

which would be relevant for the clinical effects of IVIG therapyThis study has shown that IVIG administration clearly modu-

seen in patients with primary hypogammaglobulinemia. It is likelylates cytokine release, but another question that remains unclear is

that this effect, combined with other postulated mechanisms ofwhether IVIG therapy could shift the cytokine expression pattern

action, might be of importance for the clinical immunomodulatingtoward factors mediating cytotoxicity (T-helper [Th]1 responses:

properties of IVIG in several immune-mediated disorders.IL-2, IFNγ) or those regulating humoral immunity (Th2 responses:IL-4, IL-5, IL-6, IL-10). Andersson et al.[8] found no evidence in

Acknowledgmentsvitro of an influence of IVIG on the balance of Th cells (Th1/Th2).On the other hand, studies in patients with atopic dermatitis[26] or The authors have no conflicts of interest that are directly relevant to the

contents of this manuscript. This study was financed by grants from Grifolsautoimmune diseases, such as childhood idiopathic thrombo-Laboratories SA (Barcelona, Spain) and RedRespira (ISCiii RTYC-CO3/11).cytopenic purpura (ITP),[27] have shown that these patients have aThe authors wish to thank Emilia Mur and Sara Lopez, outpatient nurses, forTh1 or Th2 polarized basal pattern, although responses to IVIGtheir kind assistance and collaboration in this research work.

therapy are divergent. Huang et al.[26] did not observe a variation inthe Th1/Th2 ratio, but Mouzaki et al.[27] observed that IVIG

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