| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
*
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
Biomedical Research Institute, Rockville, MD 20852; and
Institute for Genetics, University of Cologne, Weyertal, Cologne, Germany
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
, IL-2, IL-1ß, and TNF-
mRNA
expression in liver and elevated Th1-type cytokine production by
lymphoid cells. Despite developing an enhanced Th1-type cytokine
response, the IL-10T mice showed no consistent decrease in their
Th2-type cytokine profile. Surprisingly, although granulomatous
inflammation was enhanced at the acute stage of infection, the livers
of IL-10T mice displayed no significant increase in fibrosis and
underwent normal immune down-modulation at the chronic stage of
infection. Moreover, the down-modulated state could be induced in
IL-10T mice by sensitizing the animals to schistosome eggs before
infection, further demonstrating that the major down-regulatory
mechanism is not dependent upon IL-10. We conclude that while IL-10
plays an important role in controlling acute granulomatous
inflammation, it plays no essential role in the process of immune
down-modulation in chronic schistosome infection. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
, TNF-, and IL-12. IL-10 is
also important in suppressing inflammation in a murine model of
allergic bronchopulmonary aspergillosis (4) and reduces lung injury and
increases survival in Pseudomonas aeruginosa pneumonia (5).
Recent studies have shown that the cytokine can suppress both Th1- and
Th2-associated cytokine responses in the lungs of mice exposed to
either schistosome eggs (6) or the opportunistic fungal pathogen
Aspergillus fumigatus (4). Thus, IL-10 appears to play a
critical role in regulating the host responses to a wide variety of
different pathogens.
In Schistosomiasis mansoni, CD4+
lymphocytes are central in orchestrating the formation and growth of
hepatic granulomas, and cytokines direct the inflammatory response
around the schistosome eggs. Th2 cytokine expression becomes dominant
shortly after egg laying begins, with IL-4, IL-5, IL-10, and IL-13
being the principal cytokines secreted by lymphoid cells after
stimulation with schistosome egg Ags (7). The secretion of Th1
cytokines, IFN- and IL-2, is concurrently down-regulated at the time
when Th2 responses are reaching their peak, and it has been postulated
that the down-regulation of the Th1 response begins the transition into
the chronic stage of infection, which is noted by reduced granuloma
formation around newly deposited eggs and reduced cytokine expression
by CD4+ T cells. This change in pathology mirrors a similar
alteration in tissue responsiveness that occurs in infected patients.
Numerous mechanisms have been postulated for this down-modulation,
including a role for CD8+ T cells (8), anti-idiotypic
Abs (9), B cells (10), and IL-10 (11). Interestingly, the
down-regulated state can be reversed in mice by treatment
with exogenous IL-2, IL-4, or TNF-, suggesting that the
down-modulatory mechanism is linked to the expression of these
cytokines (12, 13, 14).
Given the known counter-regulatory role of IL-10 in Th1 response
development, it was hypothesized that the cytokine probably plays a
critical role in the down-modulatory process. Neutralization studies
performed in vitro have shown that blocking IL-10 can restore IFN-
production in spleen cells from infected mice (15). IL-10 was
demonstrated to act primarily on the APC population, since
neutralization of IL-10 increased costimulatory molecule expression and
restored the ability of granuloma-derived macrophages to activate
egg-specific Th1 clones (16, 17). Moreover, exogenous IL-10 has been
shown to significantly suppress pulmonary granuloma formation
(18).
Because schistosomiasis causes significant morbidity and mortality, and severe disease is associated with defective regulation in the human population that it affects, a thorough understanding of the process of immune down-modulation might lead to more effective strategies for immunologic intervention of disease. Therefore, in the present study we have focussed on the role of IL-10 in regulating hepatic granuloma formation and fibrosis induced by schistosome infection. In these studies, wild-type and IL-10-deficient (IL-10T) mice (19) were infected and compared for changes in infection intensity, egg production, granulomatous inflammation, hepatic fibrosis, and Th1/Th2 cytokine profiles both in vitro and in vivo. Moreover, acute and chronic infections were investigated to determine whether IL-10 plays a critical role in the process of immune down-modulation, as has been hypothesized.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The IL-10-deficient mice used in these studies were originally generated on the 129J background and were back-crossed on the C57BL/10 background (19). The colony was maintained by intercrossing the fifth generation male and female heterozygous offspring. The wt, heterozygous (HET), and IL-10T littermates between 8 and 14 wk of age were used in all experiments. All mice were housed in a National Institutes of Health American Association for the Accreditation of Laboratory Animal Care-approved animal facility and were maintained on water containing antibiotics (Bactrim) (Roche Laboratory, Nutley, NJ) to reduce the occurrence of enterocolitis. Signs of enterocolitis and rectal prolapse were detected in approximately 20% of IL-10-deficient animals by 20 wk of age. We observed no increased or decreased frequency of enterocolitis as a result of S. mansoni infection. Nevertheless, it is remains possible that the enterocolitis in some mice could in part be contributing to the findings reported in infected IL-10T mice. All data, including measurements of fibrosis, infection intensity, tissue egg load, tissue eosinophilia, and liver cytokine mRNA levels, were compared to those from uninfected wt and IL-10T age-matched controls. Cercariae of S. mansoni (NMRI strain) were obtained from infected Biomphalaria glabrata snails (Biomedical Research Institute, Rockville, MD). Soluble egg (SEA) and soluble worm (SWAP) Ag preparations were derived from homogenized eggs and adult parasites as previously described (20).
Parasitology and histopathology
Mice were infected by percutaneous exposure of tail skin for 40 min in water containing between 20 and 25 cercariae. In some experiments, animals were sensitized to schistosome eggs before infection by injecting 5000 purified eggs i.p. on three occasions separated by 2 wk (20). No mortality was detected in either egg-sensitized wt or IL-10-deficient animals up to 8 wk postinfection. Mice were killed with i.p. pentobarbitol (18 mg; Sigma, St. Louis, MO) at the weeks indicated, spleens and mesenteric nodes were removed aseptically, liver biopsies were taken for mRNA isolation, and the portal system was perfused with citrated saline. The number of schistosome eggs in the liver and gut and the collagen content of the liver, determined as hydroxyproline, were measured as described previously (21). Approximately one-half of the liver was fixed in Bouin-Hollande solution, and histologic sections were processed and stained with Giemsa (Histo-Path of America, Clinton, MD). The diameters and eosinophil content of granulomas surrounding single, mature, and viable eggs were measured using an ocular micrometer, and the volume of each granuloma was calculated assuming a spherical shape.
Lymphocyte culture and cytokine assays
For in vitro cytokine measurements, single cell suspensions of
mesenteric lymph nodes and spleens were prepared aseptically at various
times after infection. Mesenteric nodes were pooled from four or five
animals per group, while spleens were processed individually. Cells
were plated in 24-well tissue culture plates at a final concentration
of 3 x 106 cells/ml in RPMI supplemented with 2
mM glutamine, 25 mM HEPES, 10% FCS, 50 µM 2-ME, penicillin, and
streptomycin. Cultures were incubated at 37°C in an atmosphere of 5%
CO2. Cells were stimulated with SEA at 20 µg/ml, with
SWAP at 50 µg/ml, or with Con A at 5 µg/ml. Supernatant fluids were
harvested at 72 h and assayed for cytokine activity. IFN-,
IL-5, and IL-10 were measured by specific two-site ELISA as previously
described (20). IL-4 levels were determined by proliferation of CT.4S
cells. Cytokine levels were calculated using standard curves
constructed using recombinant murine cytokines.
RT-PCR detection of cytokine mRNAs
Two 25-mg portions of each liver were combined and homogenized
in 1 ml of RNA STAT60 using a tissue Polytron (Omni International,
Waterbury, CT), and total RNA was isolated as recommended by the
manufacturer. The RNA was resuspended in diethylpyrocarbonate-treated
water and quantitated spectrophotometrically. A RT-PCR procedure was
performed as previously described (22) to determine the relative
quantities of mRNA for IFN-, IL-2, IL-1ß, IL-4, IL-5, IL-10,
TNF-, and hypoxanthine phosphoribosyl transferase. The primers and
probes for all genes were previously described (22, 23). The PCR
conditions and cycle number were strictly defined for each cytokine
primer pair, such that a linear relationship between input RNA and
final PCR product was obtained. Positive and negative controls were
included in each assay to confirm that only cDNA PCR products were
detected and that none of the reagents was contaminated with cDNA or
extraneous PCR products. The amplified DNA was analyzed by
electrophoresis, Southern blotting, and hybridization with
cytokine-specific probes. The chemiluminescent signals were quantified
using a 600 ZS scanner (Microtek International, Torrance, CA). The
amount of PCR product was determined by comparison of signal density to
that of standard curves generated from simultaneously amplified
stepwise dilutions of cDNA obtained from samples with a high amount of
specific cytokine mRNA. Fold increases for individual samples were
calculated as the reciprocal of the equivalent dilution of control
(uninfected mouse liver) cDNA. Amplification of hypoxanthine
phosphoribosyl transferase served as an internal control for the amount
of RNA and cDNA from each sample.
Statistics
Schistosome worm and egg numbers, changes in cytokine mRNA, and values for secreted cytokine proteins were compared using Student’s two-tailed t test. Hepatic fibrosis was compared by analysis of covariance, using the log of total liver eggs as the covariate and the log of hydroxyproline per egg. p < 0.05 was regarded as significant. A minimum of three separate experiments were performed for all data presented.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
To evaluate the regulatory role of IL-10 in S.
mansoni egg-induced liver pathology, we infected wt, HET, and
IL-10T littermates percutaneously with 25 S. mansoni
cercariae. The animals were sacrificed 8 and 14 wk postinfection and
examined for several parasitologic and immunologic parameters. As shown
in Table I
, all three groups of mice
harbored similar worm numbers, and tissue eggs produced per worm pair
did not vary among the groups at any time point examined. At 8 wk
postinfection, the time of the peak tissue response, the IL-10T mice
displayed between a 30 and 40% increase in the average volume of
hepatic granulomas compared with their wt littermates (Fig. 1). Furthermore, the HET litter mates
developed a number of granulomas intermediate between those of the wt
and IL-10T mice, suggesting a possible gene dosage effect for IL-10
activity. As is characteristic for acute granulomas, the lesions in wt
and HET mice contained large numbers of eosinophils (Table I).
Nevertheless, the granulomas in IL-10T animals exhibited a significant
reduction in their eosinophil composition. There was also an increase
in central necrosis in granulomas surrounding the eggs in IL-10T vs wt
mice. The degree of fibrosis (measured by hydroxyproline) was evaluated
in the animals, and again, despite having a significantly enhanced
inflammatory response, the levels of hydroxyproline were consistently,
but not significantly, lower in IL-10T vs wt mice.
|
|
). Although the granulomas were still somewhat larger in the
IL-10T vs wt mice at 14 wk, the IL-10T mice also displayed a highly
significant reduction in the size of their lesions (46% reduction from
8 wk). There were no obvious differences in the cellular composition of
the granulomas in any of the groups at 14 wk postinfection, and despite
seeing higher fibrosis in involuting granulomas, there were no
significant differences detected between wt and IL-10T mice in this
parameter (Table I). IL-10-deficient mice display an altered cytokine response during the acute, but not the chronic, stage of infection
We have shown previously that the development of pulmonary
schistosome egg granulomas is highly dependent upon type 2 cytokine
production (24). Nevertheless, the role of Th1- vs Th2-associated
cytokines in hepatic lesion formation during infection remains highly
controversial (11, 13, 20, 21, 25, 26, 27). To determine whether an altered
cytokine response might be playing a role in the enhanced granulomatous
response seen at 8 wk in IL-10T mice, we isolated the mesenteric lymph
nodes and spleens from 8- and 14-wk-infected mice; cultured the
isolated lymphocytes in the presence of SEA, SWAP, or mitogen (Con A);
and then assayed the supernatants for the production of IFN-, IL-5,
IL-4, and IL-10. As expected, wt lymphocytes obtained from lymph nodes
(Fig. 2A) and spleens
(not shown) exhibited a highly polarized type 2 cytokine pattern in
response to SEA, SWAP, and mitogen at 8 wk, displaying high levels of
IL-4, IL-5, and IL-10, but very low levels of IFN-. In contrast, the
lymphocytes from IL-10T mice demonstrated a mixed Th1/Th2 profile of
cytokine expression, since IFN- levels were increased in response to
both Ags and mitogen, while levels of IL-4 and IL-5 were modestly, but
variably, decreased compared those in their wt littermates. A similar
mixed profile of cytokine expression was reported in the lymph nodes
draining the lungs of IL-10T mice injected i.v. with schistosome eggs
(6). The HET mice displayed a profile of cytokine expression that was
either similar to that of their wt littermates or intermediate between
those of wt and IL-10T mice.
|
production was virtually undetectable in all three
groups of mice, showing a dramatic reduction from the levels observed
at 8 wk in the IL-10T mice (Fig. 2B). IL-10
production was similarly down-regulated in both wt and HET animals by
14 wk, and in the experiment shown was completely absent in the
response to both Ag and mitogen restimulation. IL-4 and IL-5 production
also tended to be lower at 14 vs 8 wk in wt and HET mice and was not
significantly or consistently different in the IL-10T animals at this
later time point. Thus, although the wt and IL-10T mice displayed
dramatically altered cytokine profiles at the acute stage, as the
infection proceeded into the chronic phase, these differences were
diminished, and all wt, HET, and IL-10T mice developed reduced, but
polarized, Th2-type cytokine responses. IL-10T mice exhibit an altered cytokine mRNA response in situ at the site of acute granuloma formation
To determine whether a similar alteration in cytokine expression
was observed in vivo at the site of granuloma formation during the
acute stage of infection, we isolated liver mRNA at 8 wk and
performed quantitative RT-PCR. As shown in Figure 3, wt mice displayed increases in IL-4,
IL-5, and IL-10 mRNA, but only modest increases in the expression of
IFN-, IL-2, IL-1ß, and TNF- at this time point. IL-10T mice, in
contrast, showed nearly an average 10-fold increase in IFN- and IL-2
mRNA production and between a 3- to 4-fold increase in both IL-1ß and
TNF- compared with those in their wt littermates. Although the
expression of IL-4 mRNA was decreased in IL-10T vs wt mice
approximately 3- to 4-fold in the experiment shown, this difference was
not consistently observed in the four separate experiments performed.
Thus, the pattern of cytokine mRNA expression observed in the livers
closely mirrored the mixed Th1/Th2 cytokine production profile observed
in the lymph nodes and spleens.
|
Our previous studies have indicated that prior exposure to
schistosome eggs can decrease acute stage granuloma formation and
reduce fibrosis in animals subsequently infected with S.
mansoni (20). Thus, egg sensitization may provide a means to more
rapidly induce the down-modulated state typically observed at more
chronic stages of infection with the parasite. To further determine
whether immune down-modulation could be established in mice deficient
in IL-10, we sensitized groups of wt and IL-10T mice to the parasite
eggs three times before exposing them to a percutaneous infection. As
shown in Figure 4, nonsensitized IL-10T
mice again showed a markedly increased granulomatous response compared
with that of their wt littermates at 8 wk postinfection. Egg
sensitization had only a modest suppressive effect on the size of
granulomas in the wt mice, while the IL-10T mice displayed a highly
significant reduction in the size of their lesions as a result of i.p.
egg sensitization, again further demonstrating that immune
down-modulation can be induced in the absence of IL-10.
|
(Fig. 5). Egg sensitization appeared to have
little or no effect on Th2-associated cytokine expression in both wt
and IL-10T mice, while in contrast, the production of IFN- in IL-10T
mice was significantly decreased as a result of prior egg exposure.
Similar changes in cytokine expression were observed in the spleen
(data not shown).
|
, IL-2,
IL-1ß, and TNF- were all increased in the IL-10T mice (Fig. 6). As seen in the spleens and mesenteric
lymph nodes, egg sensitization had little or no effect on the pattern
of cytokine expression in wt mice, while in IL-10-deficient mice, prior
egg sensitization had a dramatic and highly significant suppressive
effect on nearly every cytokine mRNA examined, except TNF-, for
which the decreases observed were not statistically significant.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Early experiments analyzing the Th1/Th2 balance in schistosome
infection revealed that Th2-type cytokines dominate the response at the
acute (patent) stage of infection, while Th1-associated cytokines are
expressed preferentially at earlier time points, before or in the first
few days of egg laying (7, 29). The switch from Th1 to Th2 cytokine
dominance coincides with patency and has been attributed to the
development of an immune response to the eggs that are first produced
by the adult female parasites between 4 and 5 wk postinfection. In
vitro studies have suggested that IL-10 is in large part responsible
for the suppression of IFN- expression in infected mice (15), a
finding that has also been observed with PBMC obtained from
infected humans (30). One hypothesis is that the early Th1-type
response is an essential component of the acute granulomatous response
and that immunomodulation occurs as a result of the down-regulation of
the Th1 response (11). IL-10, produced in large part by
granuloma-derived macrophages, was therefore hypothesized to be the
major factor leading to T cell anergy and reduced Th1 cytokine
expression in chronic schistosome infection. IL-10 was suggested to
operate in this manner by down-regulating the expression of
costimulatory molecules on APCs (16, 17).
In the current study, the role of IL-10 in murine schistosomiasis was
directly investigated by analyzing the host response in mice
genetically deficient in the cytokine (19). In our studies, we found
that steady state levels of IL-10 mRNA were significantly increased in
the livers of wt mice 8 wk postinfection and that both spleen and
mesenteric lymph node cells secreted the cytokine in response to egg Ag
restimulation in vitro. Interestingly, although IL-10-deficient animals
displayed a markedly altered cytokine response and exhibited enhanced
hepatic granuloma formation at 8 wk postinfection, the mice underwent
normal immune down-modulation at the chronic stage. At 8 wk
postinfection, IFN-, IL-2, TNF-, and IL-1ß mRNA expressions
were significantly elevated in IL-10T vs wt mouse livers undergoing
granuloma formation, and expression of IFN- was similarly increased
in the mesenteric nodes and spleens, indicating that an enhanced
Th1-type immune response was induced in the cytokine-deficient mice.
Despite having an increased Th1 response, the animals displayed only a
partial reduction in the production of Th2 cytokines, which dominated
the response in the wt animals during the acute stage. By 14 wk, the
differences between the wt and IL-10T mice in terms of both cytokine
production and granuloma size were much less obvious, and both groups
displayed primarily a Th2-dominated response and reduced IFN-
expression and granuloma formation compared to those at 8 wk (Fig. 2).
Although these data fail to demonstrate a necessary role for IL-10 in
immune down-modulation, they clearly demonstrate that IL-10 can
regulate early acute granuloma formation in schistosomiasis and suggest
that in certain situations, maximal inflammation associates with a
mixed Th2/Th1 response. Nevertheless, the particular requirement for
IFN- in hepatic granulomatous inflammation remains unclear. A recent
report examining schistosome infection in IFN--deficient mice
(C57BL/6 background) found virtually unaltered granuloma formation in
the livers at 8 wk postinfection, and the animals underwent normal
immune down-modulation at the chronic stage (31), while pulmonary
granuloma formation was enhanced in IFN--depleted i.v.
egg-challenged mice (24). Moreover, mice sensitized with eggs and IL-12
before infection exhibited much smaller granulomas while displaying a
marked increase in IFN- production (20). Thus, it is currently
unclear whether the enhanced inflammatory response in IL-10T mice is
due to increased IFN- production or possibly to the altered
expression of other factors involved in the granulomatous response.
IL-1ß and TNF- are likely candidates given their enhanced
expression in IL-10T mice (Fig. 3), and TNF- in particular has
already been demonstrated to play an important role in the
granulomatous response (14, 27). Somewhat surprisingly, the production
of several Th2-associated cytokines was only minimally down-regulated
in the IL-10T mice (Figs. 2 and 3). Therefore, it is also possible that
the reduced, but persistent, Th2 response in combination with an
enhanced Th1 response contribute to the increased lesion formation
observed during the acute stage.
Surprisingly, despite having a markedly enhanced inflammatory response
at wk 8, there was no corresponding increase in tissue eosinophilia or
fibrosis in the IL-10T vs wt mice at 8 wk. IFN- is known to suppress
collagen synthesis by fibroblasts (32), and exogenous IFN- has been
shown to suppress fibrosis in schistosome-infected mice (33).
Therefore, although the absence of IL-10 enhances the inflammatory
response, the corresponding increase in IFN- may, in turn, prevent
exacerbated fibrosis and suppress the influx of eosinophils. In support
of this conclusion, previous studies using IL-12/egg-sensitized mice
have shown that altering the Th cell response toward a Th1 response
markedly decreased hepatic fibrosis (20). Interestingly, while IFN-
was significantly increased in IL-10T mice, Th2-associated cytokines
were only partially and variably decreased. In contrast to these
observations, IL-12/egg-sensitized mice showed a sustained polarization
in the Th1 direction and showed no significant increase in Th2-type
cytokine expression even at late time points (20). Moreover, in
addition to developing less liver fibrosis, the latter animals
generated smaller egg-induced granulomas. Thus, reduced fibrosis
appears to correlate more with the presence of IFN-, while
egg-induced inflammation may be more dependent upon the production of
Th2 cytokines. These findings add to the growing evidence arguing for a
partial dissociation of granuloma size and hepatic fibrosis (34).
IFN- depletion studies in the IL-10 knockout mice could be used to
determine more directly whether the changes in granuloma formation
and/or collagen synthesis are directly controlled by this important
immunoregulatory cytokine.
In general, the observations regarding cytokine regulation in infected
IL-10T mice presented here are similar yet at the same time distinct
from observations recently described in a pulmonary granuloma model
(6). In both cases, the mutant animals developed a mixed or unpolarized
Th1/Th2-type response to schistosome eggs. Surprisingly, however, the
effects of IL-10 deficiency on the inflammatory response in both
locations were strikingly different. In the lung, where the
inflammatory response is driven primarily by Th2 cytokines (24), the
increased IFN- response in IL-10T mice resulted in an average 30%
reduction in the size of the egg-induced lesions (6). The resulting
decrease in lesion size was attributed to an increased IL-12/IFN-
response, since IL-12 neutralization restored granuloma formation to wt
levels, while markedly decreasing IFN- production. By contrast, in
schistosome-infected IL-10T mice, in which granuloma formation occurs
in liver and intestines, the mixed Th1/Th2 response was associated with
increased granuloma size during the acute stage of infection (Table I).
These observations therefore may help explain some of the conflicting
results that have been reported in studies examining granuloma
formation in the lungs vs livers of egg-injected or infected mice,
respectively (35). Despite these differences, in both cases IFN- was
associated with reducing the major pathologic manifestation found at
each site. In the lung, increased Th1 responses were associated with
less inflammation (24), while in the liver, less fibrosis was observed
(20). Together, these findings underscore the pitfalls in studying
mechanisms of disease pathogenesis in schistosomiasis based solely on
experiments involving the measurement of either pulmonary or hepatic
granuloma formation.
The current report as well as the previous study examining granuloma
formation in the lung both demonstrate that IL-10 production is
critical for polarizing the egg-induced Th2 response (6). Although
IL-10 was not required for the development of Th2 cytokine production,
the continued expression of Th2-associated cytokines despite markedly
increased IFN- production probably contributed to the survival of
schistosome-infected IL-10T mice. This conclusion is based in part on
the findings of a recent study examining schistosome infection in
IL-4-deficient mice (C57BL/6 background) (36). These mice failed to
develop a significant Th2 response and, as a result, lost weight and
exhibited signs of severe acute cachexia linked to an increased
Th1-type response. We also observed weight loss and mortality in
infected IL-10T mice, 20 to 30% of which succumbed between wk 8 and 14
postinfection (data not shown). IFN- production was also augmented
in the IL-10T mice, to levels even higher than those reported in
IL-4-deficient animals (25, 26). Nevertheless, the degree of mortality
did not reach the levels reported in the IL-4T mice, which all died
between 9 and 11 wk postinfection (36). We hypothesize that these
differences are due to the continued presence of a reduced, but
significant, Th2 response in the IL-10T mice. Thus, although Th2
cytokine expression is potentially damaging in terms of triggering
excessive fibrosis, a more modest response is necessary for granuloma
formation and appears to play an essential host-protective role in
schistosomiasis.
Together, these data demonstrate that while IL-10 is not essential for
immune down-modulation in schistosomiasis, the cytokine has an
important role in regulating early acute disease as well as the
character of the developing immune response. Interestingly, not only
did IL-10-deficient mice show normal immune down-modulation during
chronic infection, but we were able to accelerate the down-modulated
state by sensitizing these animals to the parasite eggs before
infection (Fig. 5). The sensitized mice showed reduced cytokine mRNA
expression in their livers as well as markedly reduced granuloma size
at wk 8 compared with their unsensitized IL-10T littermates. The most
striking finding in these experiments was the marked suppression of
IL-2 mRNA expression, which was reduced to almost background levels in
the egg-sensitized IL-10T animals. These findings are particularly
important since previous studies have shown that the down-modulated
state can be reversed in chronically infected mice by exogenous rIL-2
(12). Identifying the IL-10-independent mechanism for suppressing IL-2
production could lead to a more thorough understanding of the process
of immune down-modulation. Numerous other mechanisms to explain
immunomodulation have been described, including a potential role for
CD8+ T cells and immunoregulatory Ids (8, 9, 37). B cell
depletion studies have suggested a role for these cells as well in
immunomodulation (10), and recent studies examining chronic schistosome
infection in B cell-deficient mice (38) have identified a potentially
critical role for the humoral response in immunomodulation. Thus,
although these data demonstrate that IL-10 is an important
immunoregulatory cytokine in acute schistosomiasis, other mechanisms
clearly play a more critical role in the important process of immune
down-modulation.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Abbreviations used in this paper: wt, wild type; IL-10T mice, IL-10-deficient mice; HET, heterozygous; SEA, soluble egg Ag; SWAP, soluble adult worm Ag.
Received for publication October 15, 1997. Accepted for publication January 6, 1998.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
, and TNF-. J. Immunol. 157:798.[Abstract]
restores granulomas and induces parasite egg-laying in schistosome-infected SCID mice. Nature 356:604.[Medline]
deficient mice chronically infected with Schistosoma mansoni. Infect. Immun. 65:2583.[Abstract]
-Interferon treatment inhibits collagen deposition in murine schistosomiasis. Hepatology 10:795.
-mediated cachexia and death during acute schistosomiasis. J. Immunol. 159:777.[Abstract]
This article has been cited by other articles:
|
|
 |
|
  A. Balic, Y. M. Harcus, M. D. Taylor, F. Brombacher, and R. M. Maizels IL-4R signaling is required to induce IL-10 for the establishment of Th2 dominance Int. Immunol., October 1, 2006; 18(10): 1421 - 1431. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. F. Hassan, Y. Zhang, C. R. Engwerda, P. M. Kaye, H. Sharp, and Q. D. Bickle The Schistosoma mansoni Hepatic Egg Granuloma Provides a Favorable Microenvironment for Sustained Growth of Leishmania donovani Am. J. Pathol., September 1, 2006; 169(3): 943 - 953. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. Taylor, M. Mohrs, and E. J. Pearce Regulatory T Cell Responses Develop in Parallel to Th Responses and Control the Magnitude and Phenotype of the Th Effector Populatio J. Immunol., May 15, 2006; 176(10): 5839 - 5847. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Baumgart, F. Tompkins, J. Leng, and M. Hesse Naturally Occurring CD4+Foxp3+ Regulatory T Cells Are an Essential, IL-10-Independent Part of the Immunoregulatory Network in Schistosoma mansoni Egg-Induced Inflammation J. Immunol., May 1, 2006; 176(9): 5374 - 5387. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Yao, W. Li, M. H. Kaplan, and C.-H. Chang Interleukin (IL)-4 inhibits IL-10 to promote IL-12 production by dendritic cells J. Exp. Med., June 20, 2005; 201(12): 1899 - 1903. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. E. Mangan, R. E. Fallon, P. Smith, N. van Rooijen, A. N. McKenzie, and P. G. Fallon Helminth Infection Protects Mice from Anaphylaxis via IL-10-Producing B Cells J. Immunol., November 15, 2004; 173(10): 6346 - 6356. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. McKee and E. J. Pearce CD25+CD4+ Cells Contribute to Th2 Polarization during Helminth Infection by Suppressing Th1 Response Development J. Immunol., July 15, 2004; 173(2): 1224 - 1231. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Smith, C. M. Walsh, N. E. Mangan, R. E. Fallon, J. R. Sayers, A. N. J. McKenzie, and P. G. Fallon Schistosoma mansoni Worms Induce Anergy of T Cells via Selective Up-Regulation of Programmed Death Ligand 1 on Macrophages J. Immunol., July 15, 2004; 173(2): 1240 - 1248. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Barbarin, M. Arras, P. Misson, M. Delos, B. McGarry, S. H. Phan, D. Lison, and F. Huaux Characterization of the Effect of Interleukin-10 on Silica-Induced Lung Fibrosis in Mice Am. J. Respir. Cell Mol. Biol., July 1, 2004; 31(1): 78 - 85. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. P. Beiting, S. K. Bliss, D. H. Schlafer, V. L. Roberts, and J. A. Appleton Interleukin-10 Limits Local and Body Cavity Inflammation during Infection with Muscle-Stage Trichinella spiralis Infect. Immun., June 1, 2004; 72(6): 3129 - 3137. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hesse, C. A. Piccirillo, Y. Belkaid, J. Prufer, M. Mentink-Kane, M. Leusink, A. W. Cheever, E. M. Shevach, and T. A. Wynn The Pathogenesis of Schistosomiasis Is Controlled by Cooperating IL-10-Producing Innate Effector and Regulatory T Cells J. Immunol., March 1, 2004; 172(5): 3157 - 3166. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. B. Stavitsky Regulation of Granulomatous Inflammation in Experimental Models of Schistosomiasis Infect. Immun., January 1, 2004; 72(1): 1 - 12. [Full Text] [PDF]
|
|
|
|
|
|
S. K. Bliss, A. Alcaraz, and J. A. Appleton IL-10 Prevents Liver Necrosis During Murine Infection with Trichinella spiralis J. Immunol., September 15, 2003; 171(6): 3142 - 3147. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. d. S. Pyrrho, J. A. Ramos, R. M. Neto, C. S. d. Silva, H. L. Lenzi, C. M. Takiya, and C. R. Gattass Dexamethasone, a Drug for Attenuation of Schistosoma mansoni Infection Morbidity Antimicrob. Agents Chemother., November 1, 2002; 46(11): 3490 - 3498. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. E. Jones, M. R. Ackermann, U. Wille, C. A. Hunter, and P. Scott Early Enhanced Th1 Response after Leishmania amazonensis Infection of C57BL/6 Interleukin-10-Deficient Mice Does Not Lead to Resolution of Infection Infect. Immun., April 1, 2002; 70(4): 2151 - 2158. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. K. Lundy and D. L. Boros Fas Ligand-Expressing B-1a Lymphocytes Mediate CD4+-T-Cell Apoptosis during Schistosomal Infection: Induction by Interleukin 4 (IL-4) and IL-10 Infect. Immun., February 1, 2002; 70(2): 812 - 819. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Vaillant, M. G. Chiaramonte, A. W. Cheever, P. D. Soloway, and T. A. Wynn Regulation of Hepatic Fibrosis and Extracellular Matrix Genes by the Th Response: New Insight into the Role of Tissue Inhibitors of Matrix Metalloproteinases J. Immunol., December 15, 2001; 167(12): 7017 - 7026. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Pedras-Vasconcelos, L. R. Brunet, and E. J. Pearce Profound effect of the absence of IL-4 on T cell responses during infection with Schistosoma mansoni J. Leukoc. Biol., November 1, 2001; 70(5): 737 - 744. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. I. Restrepo, J. I. Alvarez, J. A. Castano, L. F. Arias, M. Restrepo, J. Trujillo, C. H. Colegial, and J. M. Teale Brain Granulomas in Neurocysticercosis Patients Are Associated with a Th1 and Th2 Profile Infect. Immun., July 1, 2001; 69(7): 4554 - 4560. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Martin, K. Caspersen, and J. S. Dumler Immunopathology and Ehrlichial Propagation Are Regulated by Interferon-{{gamma}} and Interleukin-10 in a Murine Model of Human Granulocytic Ehrlichiosis Am. J. Pathol., May 1, 2001; 158(5): 1881 - 1888. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. G. P. Ross, A. C. Sleigh, Y. Li, G. M. Davis, G. M. Williams, Z. Jiang, Z. Feng, and D. P. McManus Schistosomiasis in the People's Republic of China: Prospects and Challenges for the 21st Century Clin. Microbiol. Rev., April 1, 2001; 14(2): 270 - 295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ramaswamy, P. Kumar, and Y.-X. He A Role for Parasite-Induced PGE2 in IL-10-Mediated Host Immunoregulation by Skin Stage Schistosomula of Schistosoma mansoni J. Immunol., October 15, 2000; 165(8): 4567 - 4574. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Holscher, M. Mohrs, W. J. Dai, G. Kohler, B. Ryffel, G. A. Schaub, H. Mossmann, and F. Brombacher Tumor Necrosis Factor Alpha-Mediated Toxic Shock in Trypanosoma cruzi-Infected Interleukin 10-Deficient Mice Infect. Immun., July 1, 2000; 68(7): 4075 - 4083. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. F. Hoffmann, A. W. Cheever, and T. A. Wynn IL-10 and the Dangers of Immune Polarization: Excessive Type 1 and Type 2 Cytokine Responses Induce Distinct Forms of Lethal Immunopathology in Murine Schistosomiasis J. Immunol., June 15, 2000; 164(12): 6406 - 6416. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. W. Mola, I. O. Farah, T. M. Kariuki, M. Nyindo, R. E. Blanton, and C. L. King Cytokine Control of the Granulomatous Response in Schistosoma mansoni-Infected Baboons: Role of Exposure and Treatment Infect. Immun., December 1, 1999; 67(12): 6565 - 6571. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. F. Hoffmann, S. L. James, A. W. Cheever, and T. A. Wynn Studies with Double Cytokine-Deficient Mice Reveal That Highly Polarized Th1- and Th2-Type Cytokine and Antibody Responses Contribute Equally to Vaccine-Induced Immunity to Schistosoma mansoni J. Immunol., July 15, 1999; 163(2): 927 - 938. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. G. Fallon and D. W. Dunne Tolerization of Mice to Schistosoma mansoni Egg Antigens Causes Elevated Type 1 and Diminished Type 2 Cytokine Responses and Increased Mortality in Acute Infection J. Immunol., April 1, 1999; 162(7): 4122 - 4132. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Montesano, D. G. Colley, M. T. Willard, G. L. Freeman Jr., and W. E. Secor Idiotypes Expressed Early in Experimental Schistosoma mansoni Infections Predict Clinical Outcomes of Chronic Disease J. Exp. Med., May 6, 2002; 195(9): 1223 - 1228. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
