339 Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 101(Suppl. I): 339-343, 2006
Schistosoma mansoni antigen-driven interleukin-10 production in
infected asthmatic individuals
Luciana S Cardoso, Sergio C Oliveira**, Lucila GG Pacífico**, Alfredo M Góes**,
Ricardo R Oliveira, Cristina T Fonseca**, Edgar M de Carvalho/*, Maria Ilma Araújo/*/+
Serviço de Imunologia, Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Rua João das Botas s/no,
5o andar, 40110-160 Salvador, BA, Brasil *Escola Bahiana de Medicina e Saúde Pública, Salvador, BA, Brasil **Instituto de
Ciências Biológicas, Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG,
and Instituto de Investigação em Imunologia (iii)/Milenio, Brasil
Asthmatics infected with Schistosoma mansoni have a less severe course of asthma and an inhibition of the Th2
inflammatory response that seems to be mediated by interleukin (IL-10). The objective of this study was to evaluate
the capacity of some S. mansoni antigens to stimulate IL-10 production in vitro by cells of asthmatic infected
individuals. Peripheral bloods mononuclear cells were stimulated with the S. mansoni recombinant antigens Sm22.6,
Sm14, P24, and PIII antigen. IL-10 was measured in the supernatants of cultures. As the recombinant antigens were
cloned in Escherichia coli, we blocked contaminant endotoxin with polymyxin B added to the cultures. We demon-
strated that all antigens used drove high production of IL-10 in S. mansoni infected individuals (n = 13, 408 ± 514
and 401 ± 383 pg/ml, 484 ± 245 pg/ml, 579 ± 468 pg/ml, respectively). In asthmatics infected with S. mansoni (n =
21) rP24 induced higher levels of IL-10 (565 ± 377 pg/ml) when compared to PIII, rSm14 and rSm22.6 (184 ± 209
pg/ml; 292 ± 243 pg/ml; 156 ± 247 pg/ml, respectively). Conclusion: the S. mansoni antigens evaluated in this study
stimulated IL-10 production by cells from infected individuals and therefore they have the potential to be used as a
modulator of the inflammatory response in asthma.
Key words: Schistosoma mansoni recombinant proteins - S. mansoni antigens - interleukin-10
Evidences has accumulated that helminth infections
protect against the development of allergy. For instance
Lynch et al. (1993) demonstrated an inhibition of the skin
prick test response to aeroallergens in individuals infected
with Ascaris lumbricoides, and that the anti-helminthic
treatment resulted in an increase in the prevalence of posi-
tive skin tests. These findings were supported by others
authors (van den Biggelaar et al. 2000) and in the last few
years some studies have demonstrated that Schistosoma
mansoni infection not only suppresses the skin prick test
response, but modulates asthma severity (Araujo et al.
2000, van den Biggelaar et al. 2000, 2001, 2004, Medeiros
et al. 2003).
Asthma is a multifatorial disease that results from ge-
netic predisposition, exposure to allergens and environ-
mental factors. While some environmental factors precipi-
tate the development of asthma, others seem to be pro-
tective. This is the case of helminth infections, particu-
larly S. mansoni, which through the modulation of the
inflammatory response prevent asthma (Medeiros et al.
2003, Araujo et al. 2004). Studying the mechanisms be-
hind the protection against allergy, Araujo et al. (2004)
found that interleukin (IL-10) seems to play an important
role in modulating the Th2 inflammatory response involved
in the pathology of allergic diseases. Supporting this idea,
Bigellar et al. showed high levels of this cytokine in indi-
viduals infected with S. haematobium who did not re-
spond to skin test to aeroallergens (van den Biggelaar et
It is well known that the acute phase of S. mansoni
infection is characterized by a strong Th1 inflammatory
response that evolues to a parasite antigen-driven Th2
response cronically (Grzych et al. 1991, Pearce et al. 1991).
It is also known that this down modulation is mediated by
S. mansoni antigen-driven IL-10 production (Sher et al.
1991). IL-10 is an anti-inflammatory cytokine produced
by a variety of cells such as macrophages, T CD4+, T
CD8+ and T CD4+CD25+ cells. While in the chronic phase
of S. mansoni infection IL-10 is produced in high levels
(Gazzinelli & Colley 1992, Williams et al. 1994, Araujo et al.
1996), in asthma, despite the immune response being the
Th2 type, the production of IL-10 is impaired. Studies have
shown that IL-10 is protective against asthma, and in-
creases in levels during immunotherapy (Akdis et al. 1998).
The protective role of IL-10 in asthma include the induc-
tion of IgG4 (Jeannin et al. 1998), down-modulation of
Th2 cytokine production (Araujo et al. 2004) and the inhi-
bition of histamine and other inflammatory mediators by
mast cells (Royer et al. 2001).
Considering the potential of S. mansoni antigens in
protecting against allergic diseases, this study aimed to
evaluate some parasite antigens regarding their ability to
induce IL-10 production. The S. mansoni antigens evalu-
ated were Sm22.6, a soluble protein from the tegument,
present in all life cycle of the worm with the exception of
egg (Jeffs et al. 1991). Sm14 is a fatty-acid binding protein
from the adult worm (Moser et al. 1991). PIII is a fraction
Financial support: CNPq, NIH grant D43TW06216, NIH/
Fogarty grant D43 TW00919
+Corresponding author: email@example.com
Received 25 May 2006
Accepted 26 June 2006
340 S. mansoni antigen-driven IL-10 production • Luciana S Cardoso et al.
of S. mansoni soluble adult worm antigen (SWAP) (Hirsch
& Goes 1996). This antigen is associated with down-regu-
lation of granuloma formation in vitro (Oliveira et al. 1999)
and P24, fraction of PIII that also modulates granuloma
size in murine models (Zouain et al. 2000, 2002).
MATERIALS AND METHODS
This study evaluated the ability of some S. mansoni
antigens in inducing IL-10 production by peripheral blood
mononuclear cells (PBMC) of individuals chronically in-
fected with S. mansoni living in an endemic area in Bahia,
Brazil. It was included 34 individuals from 6 to 40 years of
age infected with S. mansoni and other helminths, such
as A. lumbricoides, Trichuris trichiura, and hookworm.
From these individuals 21 had asthma. The Table shows
demographic data and S. mansoni parasite burden in the
ng/ml) and with the mitogen phytohemaglutinin (PHA, at
a final dilution of 1:100) were used as controls. Cultures
stimulated with LPS were incubated at 37°C, 5% CO2 for 6,
12, 24, and 48 h, while cultures stimulated with S. mansoni
antigens and PHA were incubated for 48 h. After incuba-
tion, the supernatants were collected and maintained at –
20°C, for later measurement of IL-10. Levels of IL-10 were
determined by an ELISA sandwich technique, using com-
mercially available kits (R&D Systems), and the results
were expressed in picograms per milliliter based on a stan-
Addition of polymyxin B to the cultures - Suspension
of PBMC (3x106 cells/ml) were pre-incubated with Poly-
myxin B (Calbiochem, Germany) in the concentration of
10 and 20 µg/ml for 30 min at 37°C, 5% CO2. They were
then incubated with the different recombinant antigens
(10 µg/ml) or LPS (0.14 ng/ml) and the cultures were incu-
bated for 6 to 48 h as described above. Polymyxin B (10 or
20 µg/ml) was also added to cultures every 12 h.
Statistical analysis - Wilcoxon matched pairs test were
used to compare the levels of IL-10 in supernatants of
PBMC cultures with or without Polymyxin B. Kruskal-
Wallis test was used to compare the levels of Il-10 in-
duced by the different antigens. Statistical significance
was established at the 95% confidence interval.
Effect of PMB in block the effect of LPS in induce IL-
10 production - The production of IL-10 in 6, 12, 24, and
48 h-cultures stimulated with LPS in the presence or ab-
sence of PMB is shown in Fig. 1. Compared to cultures
without PMB, there was a significant reduction in the lev-
els of IL-10 by addition of this antibiotic to the cultures in
all time-points evaluated. The mean levels of IL-10 in cul-
tures without PMB were 314 ± 341 pg/ml, 469 ± 364 pg/ml
and 317 ± 378 pg/ml at 12, 24, and 48 h of cultures, and
after the addition of PMB the levels decreased to 15.6 ±
9.5 pg/ml (p = 0.06), 38 ± 55 pg/ml (p = 0.03) and 15,6 ± 9.5
pg/ml (p = 0.03). The reductions in IL-10 production in
cultures of 12, 24, and 48 h were 95.0, 91.2, and 95.1%,
Demographic data from individuals infected with Schistosoma
mansoni asthmatics and nonasthmatics
Infected subjects Asthmatic infected
(n = 13)Subjects subjects (n = 21) p value
Median age (y)13 (6-40)11 (6-40)> 0,05
(% of male)
58% 46.1%> 0,05
330 ± 29852 ± 54< 0,05
The Ethical Committee of the Climério de Oliveira Hos-
pital/Federal University of Bahia approved the present
study, and an informed consent was obtained from all
study participants or their legal guardians.
S. mansoni antigens - The antigens used in this study
included three recombinant proteins, Sm22.6, Sm14, and
P24, a fraction of S. mansoni soluble adult worm antigen
(SWAP) obtained by anionic chromatography (FPLC),
named PIII, besides SWAP and SEA (soluble egg anti-
gen). The proteins were provided by the Institute of Bio-
logical Science, Departament of Biochemistry and Immu-
nology, UFMG, Brazil. The recombinant proteins were
cloned in E. coli and they were tested for lipopolysac-
charide (LPS) contamination using a commercially avail-
able LAL Chromogenic Kit (CAMBREX). The levels of
LPS were bellow 0.25 ng/ml (Sm22.6 = 0.132 ng/ml, Sm14 =
0.210 ng/ml and P24 = 0.135 ng/ml).
Cell culture and cytokine measurement - PBMC were
obtained through the Ficoll-Hypaque gradient and ad-
justed to a concentration of 3 x 106 cells/ml in RPMI 1640
containing 10% of normal human serum (AB+, heat-
inativated), 100 U/ml penicillin, 100 mg/ml streptomycin, 2
mM L-glutamine, 30 mM HEPES (all from Life technolo-
gies GIBCO BRL, Gaithersburg, MD). Cells were cultured
in vitro with antigens Sm22.6, Sm14, P24, PIII, SWAP, and
SEA (10 µg/ml) in the presence or absence of Polymyxin B
(10µg/ml) in order to neutralize the effect of LPS in induce
cytokine production. Cultures stimulated with LPS (0.15
Fig. 1: effect of Polymyxin B on LPS-induced cytokine production
in vitro. PBMCs of individuals chronically infected with Schisto-
soma mansoni (n = 6) were cultured with LPS (0.15 ng/ml) in the
presence or absence of Polymyxin B (PMB, 10 µg/ml). IL-10 was
measured using a sandwich ELISA technique. There was a signifi-
cant reduction in the levels of IL-10 when PMB was added to the
cultures (p < 0.05).
341Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 101(Suppl. I), 2006
Polymyxin B was used in the concentration of 10 and
20 µg/ml of cultures and similar levels of reduction in
cytokine production were observed (data not shown).
Therefore, we decided to use the lower concentration of
PMB (10 µg/ml of cultures) in cultures stimulated with S.
mansoni recombinant antigens. We tested the viability of
cells in cultures with Polymyxin B using trypan blue stain
and observed that the viability was about 98%.
Production of IL-10 in cultures stimulated with S.
mansoni antigens - The IL-10 production induced by S.
mansoni antigens is shown in Fig. 2. We observed that all
antigens evaluated in this study induced IL-10 produc-
tion in infected individuals (Fig. 2A). The level of this
cytokine were 408 ± 514 pg/ml to rSm22.6, 401 ± 383 pg/ml
to rSm14, 484 ± 245 pg/ml to PIII and 579 ± 468 pg/ml to
rP24 antigen. There was no significant difference in the
levels of IL-10 induced by the different antigens (p > 0,05).
In cultures stimulated with SWAP and SEA the levels of
IL-10 were 140 ± 291 pg/ml and 46 ± 43 pg/ml, respec-
Fig. 2B shows the levels of IL-10 production in asth-
matic infected individuals. Similarly, all antigen induced
IL-10 production. The levels of this cytokine in cultures
stimulated with rSm22.6, rSm14, PIII, and rP24 were 156 ±
247 pg/ml, 292 ± 243 pg/ml, 184 ± 209 pg/ml, and 565 ± 377
pg/ml. The antigen rP24 induced higher levels of IL-10
compared to the other antigens (p < 0.05). All antigens
induced higher levels of IL-10 in comparison with SWAP
and SEA (p < 0,001).
Levels of IL-10 were below the detection limit in un-
stimulated cultures, and these cytokines were detected in
high levels (≥ 1500 pg/ml) in the supernatants of PBMC
cultures stimulated with PHA (not shown).
S. mansoni infection seems to be protective against
asthma (Medeiros et al. 2003, Araujo et al. 2004). Using
mice models of S. mansoni infection it has been demon-
strated that this parasite also protects against the devel-
opment of auto-immune disease such as diabetes, experi-
mental auto-immune encephalopathy, and Crohn’s disease
(Cooke et al. 1999, Elliott et al. 2003, La Flamme et al. 2003,
Sewell et al. 2003, Zaccone et al. 2003). Some of these
studies suggest that IL-10 is a key cytokine involved in
the modulation of the inflammatory immune response ob-
served in these diseases. IL-10 is produced by cells of
individuals chronically infected with S. mansoni and there
are some S. mansoni antigens able to induce IL-10 pro-
duction in vitro. On the other hand, there is impaired pro-
duction of IL-10 in asthmatic individuals, even when their
cells are stimulated in vitro with dust mite antigens (Araujo
et al. 2004) and LPS (Borish et al. 1996, Tomita et al. 2002).
In this study we evaluated the ability of some schisto-
some vaccine candidate antigens, ie, Sm14, Sm 22.6, p24,
and PIII in induce IL-10 production by cells from asth-
matic infected individuals. Some of these antigens pro-
tect mice against liver fibrosis, the major pathology asso-
ciated with schistosomiasis, and induce IL-10 production
in individuals chronically infected with S. mansoni (Brito
et al. 2000, Zouain et al. 2000, Pacifico et al. 2006). Contrib-
uting to the choice of these antigens is the fact that they
are proteins from the tegument and do not cross react
with egg antigens, that are known to be involved in the
pathogenesis of schistosomiasis (Simpson et al. 1990).
All S. mansoni antigens used in this study induced
high levels of IL-10 by cells of individuals chronically
infected with the parasite, p24 being the major inductor of
this cytokine in asthmatic infected individuals.
Due the fact that the antigens Sm14, Sm22.6, and p24
used in this study were recombinantly cloned in E. coli,
Polymyxin B was added to the cell cultures to block the
effect of endotoxin to stimulate IL-10 production. Indeed,
the use of Polymyxin B in control cultures stimulated with
LPS completely abrogated IL-10 production. As the anti-
gens used in this study have the ability to induce IL-10
and are possibly capable of modulating the inflammatory
immune response, they may be produced in a non-bacte-
rial vector for future use as vaccines or treatment to cer-
tain immunologic-based disorders.
It is known that during S. mansoni infection cells from
the innate immune response, T cells and T regulatory cells
are able to produce IL-10 (Hesse et al. 2004). There are
some S. mansoni antigens described in the literature, such
as LNFPIII (Okano et al. 2001, Thomas et al. 2003) and
fosfatidilserine (PS) (van der Kleij et al. 2004) that also
induce IL-10 production by the cells from the innate im-
Fig. 2: production of IL-10 by PBMCs of individuals chronically infected with Schistosoma mansoni stimulated in vitro with S. mansoni
antigens (10 µg/ml). IL-10 was measured in 48 h culture supernatants using a sandwich ELISA technique. A: production of IL-10 in S.
mansoni infected individuals. The antigens rSm22.6, rSm 14, PIII, and P24 induced higher levels of IL-10 compared to SWAP and SEA (p
< 0.05); B: production of IL-10 by cells from asthmatics infected with S. mansoni. The antigens rSm22.6, rSm 14, PIII, and P24 also
induced higher levels of IL-10 compared to SWAP and SEA (p < 0.05). Levels of IL-10 in cultures stimulated with p24 were higher than
the levels observed when the cells were stimulated with rSm22.6, rSm14, and PIII (p < 0.05; denoted by an asterisk).
342S. mansoni antigen-driven IL-10 production • Luciana S Cardoso et al.
mune system. We are currently evaluating if the S. mansoni
antigens used in this study are able to induce IL-10 by
cells from uninfected asthmatics. These studies may re-
sult in new strategies to prevent allergic diseases.
To Charlton Cley Barros Castro for technical support, Elbe
Myrtes for the secretarial assistance, and Dr Daniel Morgan for
the corrections and suggestions made in the text.
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