Previous Article | Next Article 
Infection and Immunity, December 1999, p. 6565-6571, Vol. 67, No. 12
Division of Infectious Diseases, Institute of
Primate Research, National Museums of Kenya, Karen, Nairobi,
Kenya,1 and Division of Geographic
Medicine, School of Medicine, Case Western Reserve University,
Cleveland, Ohio2
Received 8 July 1999/Returned for modification 25 August
1999/Accepted 22 September 1999
Variations in exposure and treatment may contribute to
heterogeneity in immunity and granuloma-induced pathology in human schistosomiasis. To examine this hypothesis, olive baboons were either
repeatedly infected with Schistosoma mansoni cercariae or
received an equivalent dose in a single infection. They were then cured
with praziquantel and reinfected with a single exposure. Serial liver
biopsies were obtained throughout the course of the experiment, and
cytokine responses by peripheral blood mononuclear cells were measured
every 2 to 3 weeks. Reinfection after treatment resulted in a
twofold-smaller granuloma size at 6 and 9 weeks after infection
compared to the size for the same period after primary infection
(P < 0.001) but had no effect at 16 or 19 weeks postinfection. The pattern of exposure did not influence granuloma size. During primary infection schistosome-soluble egg antigen (SEA)-induced cytokine production correlated with granulomatous inflammation. Cytokine levels peaked during the acute infection, declined with chronic infection, and became undetectable after treatment. Reinfection after treatment stimulated a two- to three-fold increase in SEA-specific interleukin-4 (IL-4), IL-5, IL-10, IL-2, and
transforming growth factor Schistosomiasis is a widespread
chronic helminth infection that contributes to the death of over half a
million people yearly (30). The major form of disease
results from the chronic granulomatous response to parasite ova trapped
in host tissues. Most infected individuals, however, tolerate chronic
infection without debilitating illness. This is thought to occur
because of down-modulation of the host's granulomatous response
(30). Failure to modulate can ultimately lead to hepatic
periportal fibrosis, portal hypertension, and death. The mechanisms
associated with modulation of the granulomatous response have been the
subject of intense study and have important implications for control of
schistosome-induced liver disease and other diseases associated with
granulomatous inflammation.
The precise role that cytokines and antibodies have in regulating the
granulomatous response is not fully understood. Most of our knowledge
about the mechanisms of granuloma induction and modulation derives from
studies of the murine model of schistosomiasis. These reports show that
granuloma formation correlates with increased production of egg antigen
(Ag)-specific interleukin-4 (IL-4), IL-5, and IL-13 (6, 7, 23, 33,
47) and that its down-modulation is partially mediated by IL-10
and parasite Ag-specific antibodies (18, 26, 46).
It is unknown whether the mechanisms that regulate granulomatous
responses and disease in humans parallel those observed in murine
schistosomiasis. Human studies are limited because of the difficulty in
obtaining tissue samples in the acute phase of disease, though
observations of the immune response in chronically infected humans have
been made. Peripheral lymphocytes (or spleen cells) from asymptomatic
Schistosoma mansoni-infected patients proliferate poorly and
make little gamma interferon (IFN- Individual immune responses to schistosomiasis, however, are highly
variable, and the reasons why only some infected individuals progress
to clinically overt disease remains poorly understood. A number of
factors may contribute to the heterogeneity of immune responses and
disease observed with human schistosomiasis. Humans experience widely
different patterns of exposure to and intensity and duration of
infection, and undergo occasional treatment. Two factors in particular,
exposure and treatment, may affect the immune response and development
of disease in humans. Treatment can stimulate an acute rise in
parasite-specific antibody production (14, 36) and an
alteration in isotypes (22, 28), along with an increase in
parasite Ag-specific IFN- This study examines the hypothesis that an enhanced Th2-type immune
response induced by repeated exposure and treatment will produce worse
hepatic pathology, as indicated by larger acute and chronic granulomas
with reinfection. To examine this hypothesis, olive baboons
(Papio cynocephalus anubis) were either repeatedly infected
or received a single exposure to a comparable number of cercariae and
were allowed to develop a chronic infection (>19 weeks) before
treatment. Following reinfection animals underwent serial liver
biopsies to evaluate the granulomatous responses during the acute and
chronic phases of infection. The study describes the relationship
between schistosome-soluble egg Ag (SEA)-specific cytokine and antibody
responses in peripheral blood and the corresponding hepatic pathology
throughout the course of infection.
Animals and parasites.
Juvenile male baboons (6 to 8 kg),
P. cynocephalus anubis, were captured from schistosome-free
areas in Kenya and confirmed as infection free based on lack of
anti-schistosome antibodies as previously described (13).
Animals were maintained in open enclosures according to international
standards for primates and screened for common bacterial infections and
intestinal helminths. Any infected animals were treated at least 3 months prior to beginning the experiment (13).
Experimental protocol.
Two groups of seven juvenile baboons
each were infected percutaneously by the pouch method (38)
with either 100 cercariae weekly for a total of 10 weeks (termed
multiple infection [MI]) or 1,000 cercariae once (termed single mass
infection [SI]). After a chronic infection was established, animals
were treated orally with praziquantel (PZQ; 60 mg/kg of body weight) on
weeks 19, 27, and 30 postinfection (Fig.
1). All animals in both infection groups
were then challenged percutaneously with a single dose of 1,000 S. mansoni cercariae at week 34 postinfection and perfused 16 weeks later to recover adult worms as described previously (13). Following perfusion, 10% (by weight) of the liver and small and large intestines was sampled separately and digested in 5%
KOH to recover and count the ova (12). Peripheral venous blood was obtained every 2 to 3 weeks throughout the course of the
experiment. Cumulative stool collections were obtained weekly to
determine egg output by the Kato technique.
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Cytokine Control of the Granulomatous Response
in Schistosoma mansoni-Infected Baboons: Role of
Exposure and Treatment
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
(TGF-) production and a marked rise
in SEA-specific immunoglobulin E (IgE) and IgG regardless of the type
of exposure. Cytokine production was significantly greater in
repeatedly exposed animals (P < 0.001). SEA-induced gamma interferon production, however, did not increase with reinfection after treatment. SEA-induced TGF- was the only cytokine that remained elevated as the infection become chronic and correlated with
diminished hepatic granuloma size, implying its participation in
down-modulation. These studies demonstrate that baboons partially retain their ability to down-modulate the granulomatous response after treatment.
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
) in response to egg antigens
compared with those from (i) acutely infected individuals, (ii)
subjects after curative chemotherapy, and (iii) patients with
clinically apparent disease (9, 11, 40, 41, 48). One of the
mechanisms that contribute to the diminished Th-cell proliferation and
IFN- production results from active suppression by IL-10 (17,
20). Increased tumor necrosis factor alpha TNF-
production
(29) and a failure to adequately down-modulate lymphocyte proliferation and IFN- production correlate with development of
clinically overt hepatosplenic disease or severe bladder pathology. Down-regulation of Ag-specific IL-4 and IL-5 appears variable (16,
24, 34).
production and lymphocyte proliferation
(34, 48). The effect on Ag-specific IL-4 and IL-5 production
appears variable depending on the schistosome species and the time
after treatment that people were examined (15, 25, 34). The
effect of treatment on pathology, however, was not examined in these
studies. Other population-based studies suggest that reinfection after
interrupted treatment programs may result in worse pathology
(32). The pattern of exposure may also affect the immune
response. Our own studies of S. mansoni-infected baboons
illustrate this point. Repeatedly exposed baboons develop high levels
of egg Ag-specific IL-4, IL-5, and IFN- production by peripheral
blood mononuclear cells (PBMC) and elevated serum immunoglobulin E
(IgE) levels compared to baboons exposed once to a comparable number of
S. mansoni cercariae (31). However, a detailed
study of exposure, treatment, and reinfection for the immune and
granulomatous responses has not been previously reported.
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
View larger version (7K):
[in a new window]
FIG. 1.
Experimental design with time indicated in weeks. The
weeks listed indicate time points at which serum and PBMC were sampled.
SI, single infection of baboons with 1,000 S. mansoni
cercariae; MI, multiple infection of 100 cercariae per week for 10 consecutive weeks.
Histopathology. The details of preparation and measurement of granulomas and composition have been described elsewhere (13). Only nonconfluent granulomas containing ova at their centers were measured.
Cytokine assays.
PBMC were cultured for cytokine production
at 2 × 106/ml in complete RPMI medium (RPMI 1640, 10% fetal calf serum, 4 mM L-glutamine, 25 mM HEPES, 80 µg of gentamicin/ml) in 48-well tissue culture plates (Falcon; Becton
Dickinson Co., Franklin Lakes, N.J.). Media alone, SEA, prepared as
previously described (2) at 5 µg/ml, or the mitogens
phorbol myristate acetate (Sigma, St. Louis, Mo.) at 50 ng/ml with
ionomycin at 1 µg/ml (Behring Corp., San Diego, Calif.) were added to
cell cultures, and the cultures were incubated at 37°C in a
humidified atmosphere with 5% CO2. Supernatants were harvested after 24 h for the measurement of IL-2 and IL-4
production and on day 5 for the measurement of IL-5, IL-10,
transforming growth factor (TGF-), and IFN- production.
, the coating antibody was monoclonal antibody MAb (BMS 107)
(BioWhittaker, Walkersville, Md.) at 1 µg/ml, followed by the
detecting biotinylated MAb 7-B6-1 (Diapharma Group Inc., Franklin,
Ohio) at 0.5 µg/ml. The capture MAb used for IL-4 was 25D2 (2.5 µg/ml; Pharmingen, San Diego, Calif.), and the biotinylated MAb 8D2
(2.5 µg/ml; Pharmingen) was used for detection. The coating MAb for
IL-5 was TRFK5 (1 µg/ml; Pharmingen), and the biotinylated MAb was
5A10 (2 µg/ml; Pharmingen). For IL-10 the coating antibody used was
MAb AHC8102 (3 µg/ml; Biosource International, Camarillo, Calif.),
followed by the detecting biotinylated MAb AHC7109 (0.8 µg/ml;
Biosource International). TGF-1 was assayed as follows: the coating
antibody, MAb MAB240 (2 µg/ml; R&D Inc., Minneapolis, Minn.), was
followed by the detecting biotinylated MAb BAF24 (0.1 µg/ml; R&D
Inc.). Prior to assaying for TGF-, samples were activated by a
10-min incubation with 10 µl of 1 N HCl per 50 µl of culture
supernatants, followed by neutralization with 1.2 N NaOH-0.05 HEPES.
The coating antibody for IL-2, MAb 55.111 (4 µg/ml; R&D Inc.), was
followed by the detecting biotinylated MAb BAF202 (2.5 µg/ml;
Pharmingen). Steptavidin-alkaline phosphatase at a 1:2,000 dilution
(Jackson ImmunoResearch, West Grove, Pa.) was used as a conjugate for
all the cytokine ELISAs, while phosphatase tablets (Sigma) were used as
the substrate. Values were obtained from standard curves for human
recombinant cytokines and were expressed in picograms per milliliter.
Limits of detection were as follows: 10 pg/ml for IFN-, 20 pg/ml for
IL-4, 22 pg/ml for IL-5, 50 pg/ml for IL-2, 40 pg/ml for IL-10, and 25 pg/ml for TGF-.
Antibody assays. Levels of SEA-specific IgG and IgE in serum were measured by ELISA. The methods of detection, antibody specificity and lack of cross-reaction to other Ig isotypes have been described previously (31).
Statistical analysis. Data had a normal distribution after log transformation. Thus, all data in the experiment were analyzed for significant differences between experimental groups and control by Student's t test of log-transformed data. A paired t test was used to compare cytokine production by the same animals before and after treatment. Differences between the groups were considered significant at P < 0.05.
| |
RESULTS |
|---|
|
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
|
|---|
The effect of treatment on egg output and granuloma size after reinfection. Treatment resulted in cure of all animals based on at least two consecutive egg-negative stools as determined by the Kato technique (Fig. 2). Hepatic granuloma size was serially examined at 6, 9, and 16 weeks postinfection in the same animals, corresponding to acute (6 and 9 weeks) and chronic phases (16 weeks) of infection following PZQ treatment (Fig. 1). To limit the number of survival surgeries, a separate group of animals served as pathological controls. These animals had not been previously infected or treated and had hepatic biopsies performed at similar time points during the primary infection. Prior to treatment peak granuloma size occurred at 6 weeks postinfection, and granulomas diminished in size as the infection became chronic in animals exposed to a single infection (Fig. 3, left panel). The mean worm burdens at perfusion were 901 ± 89 in this singly infected control group. In multiply infected animals, peak granuloma size occurred at 9 weeks after primary infection (Fig. 3, right panel). However, no granulomas that warranted measurement were observed at 16 weeks postinfection. The mean worm burdens in this multiply infected control group were lower than those in singly infected control animals (767 ± 65; P < 0.05). Infection following treatment resulted in a twofold reduction in acute granuloma size in both groups (P < 0.01). Few hepatic granulomas were found in most chronically infected animals both after the primary infection and with reinfection after treatment. There was no significant difference in granuloma size among chronically infected animals. Infection following treatment resulted in significantly fewer adult worms in the previously multiply exposed baboons (161 ± 89) than in baboons in the singly infected group (466 ± 182; P < 0.05).
|
|
The effect of treatment on cytokine and antibody production after reinfection. To examine the immunological mechanisms responsible for the initiation and modulation of the granulomatous response before and after infection, peripheral venous blood was collected approximately every 3 weeks throughout the course of the experiment to examine parasite Ag and mitogen-induced cytokine production by PBMC. The mean net egg Ag-specific cytokine responses from the same baboons (two from the SI group and two from the MI group) are shown at all sampling points throughout the course of primary infection, treatment, and reinfection (Fig. 4). The mean net SEA-driven cytokine response for all seven animals, corresponding to the acute and chronic phases of the first and second infections, is shown in Table 1. The sampling points were grouped into acute- and chronic-phase points. Thus, the positive or peak cytokine response at either 6 or 9 weeks (acute phase) or at 13, 16, or 19 weeks (chronic phase) is included in the geometric mean indicated in Table 1. Mitogen-driven cytokine production was observed for a majority of animals throughout the course of the experiment, and the geometric mean for all animals in a group is shown for each cytokine (Fig. 5).
|
|
|
production peaked during the acute phase and then became
undetectable during the chronic phase of the initial infection in
representative animals (Fig. 4A). Reinfection produced a similar rise
in IFN- release during the acute infection, while the levels tended
to drop with chronic infection. The pattern of exposure, either SI or
MI, did not alter the pattern of SEA-induced IFN- production.
Geometric mean SEA-driven IFN- production levels for all the animals
had similar profiles: they were elevated during the acute phase and
declined in the chronic phase of the primary infection and with
reinfection (Table 1). Mitogen-driven IFN- production was generally
higher with reinfection than with primary infection but was equivalent
between the MI and SI groups (Fig. 5A).
Egg Ag-driven IL-2 release (Fig. 4B) peaked during the acute phase of
the primary infection and with reinfection and declined as the
infection become chronic. Reinfection resulted in two- to eightfold
more IL-2 production in both the SI and MI groups than the primary
phase (Fig. 4B and Table 1; P < 0.001). Mitogen-driven IL-2 production was higher overall with reinfection than at primary infection, particularly in multiply infected animals (Fig. 5B).
Geometric mean SEA-driven IL-4 production showed a pattern similar to
that observed for IL-2 (Fig. 4C and Table 1). SEA-driven IL-4
production was higher in the MI group than in the SI group during the
acute phase after treatment (P < 0.05). Like IL-2 and IFN-, SEA-driven IL-4 declined dramatically with chronic infection. Mitogen-driven IL-4 production levels in the primary and reinfection phases were higher in the MI group (Fig. 5C).
Peak SEA-driven IL-5 production was more variable than production of
the other cytokines. In singly infected animals it peaked at 6 weeks
(Fig. 4D) after the primary infection and 9 weeks after reinfection
(P < 0.05). In multiply infected animals peak
SEA-driven IL-5 production occurred during the chronic phase of the
first infection and 9 weeks after reinfection. These same patterns of cytokine responses were observed in all animals (Table 1). SEA-driven IL-5 production was significantly higher in the MI than in the SI group
of animals during the acute phase but not in the chronic phase after
treatment (P < 0.05) (Fig. 5D).
Egg Ag-driven IL-10 production increased two- to fivefold with
reinfection after treatment (Fig. 4E). Cytokine production peaked
during the acute phase of the infection and declined with chronic
infection after treatment in representative animals. It is notable that
egg Ag-induced IL-10 remained elevated during chronic infection after
the first infection but not after reinfection. SEA-driven IL-10
production levels were equivalent for MI and SI groups throughout the
course of the experiment.
Egg Ag-driven TGF- production was also higher with reinfection after
treatment than it was during infection prior to treatment (Fig. 4F).
Unlike the other cytokines, however, SEA-driven TGF- remained
elevated during the chronic phase of infection both before and after
treatment. Treatment eliminated the detection of SEA-driven TGF-
production in almost all animals. Overall, TGF- production levels in
SI and MI experimental groups were similar. Mitogen-driven TGF-
production was elevated with reinfection in the both groups (Fig. 5E).
Levels of SEA-specific IgE and IgG in serum. To examine the humoral correlates of modulation, levels of SEA-specific IgE, IgG, and IgM in serum were examined throughout the course of infection (Fig. 6). Egg Ag-specific IgM levels increased rapidly with the initial infection and remained at roughly the same levels throughout the course of the experiment. In contrast egg Ag-specific IgE and IgG increased significantly with reinfection after treatment and continued to rise with ongoing infection. It is notable that the rise in egg Ag-specific IgG with reinfection occurred later than that observed for egg Ag-specific IgE. Chronically infected animals with multiple infections had significantly higher levels of SEA-specific IgG and IgE in serum after treatment than singly infected animals (P < 0.05).
|
| |
DISCUSSION |
|---|
|
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
|
|---|
These studies show that reinfection following treatment resulted in acute-phase granulomas significantly smaller than those produced during the primary infection. This demonstrates the persistence of partially modulated granulomas. These results imply that treatment followed by reinfection in areas where schistosomiasis is endemic is unlikely to enhance morbidity, a finding supported by studies of both mice (8, 10) and humans (39). Since most human infections will be reinfections, the modulated state is more typical of infection in populations.
The enhanced Th2-type immune response following reinfection contradicts
our initial hypothesis that this should result in a more vigorous
granulomatous reaction, as predicted from murine studies. We further
observed that the patterns of Ag-specific cytokine production in
baboons, like those observed in infected humans (45), do not
always show a clear separation of Th1- and Th2-type immune responses,
nor do they show consistent evidence of cytokine cross-regulation
(e.g., a reciprocal decrease in IFN- with a rise in IL-4 and IL-5).
It is possible that a Th2-type response may facilitate induction of
smaller granulomas after treatment when other immunomodulatory
mechanisms have been engaged. This study indicates that SEA-driven
TGF- may contribute to down-modulation of the granulomatous
response. This was the only cytokine whose increased production
consistently correlated with diminished granuloma size. The present
observations also show that the frequency of exposure to the parasite
affects the host's immune response, consistent with our earlier
findings that repeated natural infection of baboons with S. mansoni generates higher levels of immunity than does a single
exposure (31).
It is possible that egg Ag-specific cytokine production by PBMC may not accurately reflect cytokine responses in granuloma or draining lymphoid tissues. This possibility is unlikely since PCR analysis of hepatic tissue containing granulomas tended to show a pattern of cytokine response similar to that observed in PBMC (unpublished observations). We have also observed that Ag-specific cytokine production by draining LN cells and splenocytes shows the same pattern of cytokine responses as that by PBMC. In addition, recent reports suggest that lymphocytes from the peripheral circulation migrate into and populate granulomas, where they undergo cell death by interleukin deprivation and/or apoptosis, and that egg Ag-specific lymphocytes also fail to proliferate within granulomas (35). Therefore, granulomas must contain some egg-specific lymphocytes that arise from other sites that would be represented by PBMC.
The increase in IL-2, IL-4, IL-5, IL-10, and/or TGF- with
reinfection after treatment may participate in the early suppression of
the granulomatous response. However, IL-2, IL-4, IL-5, and IL-10 are
unlikely to play a pivotal role in ongoing suppression of the
granulomatous response during chronic infection, since production of
these cytokines wanes as granulomas become smaller. The exception was
SEA-specific TGF- release. TGF- synthesis continued during the
chronic phase of infection relative to that of other cytokines. It may
suppress the granulomatous response because of its potent ability to
inhibit lymphocyte proliferation and cytokine expression and to enhance
the phagocytic activity of monocytes/macrophages within the granuloma
(21). We postulate that continued production of TGF-
during the chronic phase of infection results from expansion of egg
Ag-specific lymphocytes in gut-associated granulomas. The majority of
eggs are deposited, and the majority of granulomas are formed, in the
guts of baboons (13) and humans (4). The
gut-associated lymphoid system favors the differentiation of
lymphocytes that produce TGF- that contributes to oral tolerance
(44). Gut-derived egg Ag-specific T cells that produce
TGF- may migrate and populate hepatic granulomas and thus
participate in their down-modulation.
We failed to detect egg Ag-induced cytokine production by PBMC within 2 weeks after completion of PZQ treatment, which suggests a rapid loss of parasite-specific memory lymphocytes. Therefore, ongoing egg deposition may be necessary to maintain the cytokine and/or antibody levels required for complete modulation of the granulomatous response. The large number of ova released as a consequence of the heavy infection rapidly expands Ag-specific lymphocytes. In order to maintain lymphocyte homeostasis after generation of specific T and B cells in response to persisting infection, Ag-specific lymphocytes, including many memory cells, probably undergo accelerated cell death (37). Treatment quickly kills adult worms and abruptly stops release of ova and further stimulation of specific lymphocytes. A similar phenomenon has been observed in virus-specific CD8+ T-cell memory (27). In humans, however, schistosome Ag-specific immunity usually persists after treatment (25, 34). This may occur because of the failure to completely eradicate infection or the possibility that individuals may be rapidly reexposed after treatment. It is also possible that the generally lighter and more persistent infections observed in humans maintain detectable levels of Ag-specific memory lymphocytes without widespread cell death.
Reinfection after treatment significantly boosted parasite-specific
antibody responses, demonstrating the persistence of parasite-specific B-cell memory. It is also possible that the persisting antibody responses may contribute to modulating the acute-phase granulomatous response with reinfection. Antibodies and/or B cells have been shown to
be important in regulating the granulomatous response in mice (5,
18, 19). This modulation was shown to be, in part, Fc receptor
(FcR) dependent. Thus, antibodies may regulate the granulomatous
responses by the formation of immune complexes or anti-idiotypic
antibodies (26). This may occur at the time of egg release
after reinfection when levels of egg-Ag-specific antibodies in serum
are elevated. Immune complex binding to FcR (and complement) receptors
on macrophages, B cells, and dendritic cells can impair their ability
to present antigen (1, 13) and increase their phagocytic
activity (37); both of these functions can participate in
modulating the granuloma. TGF- can participate in this regulatory
network by its ability to up-regulate expression of cell surface
FcRIII receptors on monocytes (21).
The present study shows that repeated primary infection followed by treatment and reinfection produced a significant reduction in worm burden, compared to that in animals receiving a single exposure during their primary infection. Thus, repeatedly infected animals had approximately 65% fewer adult worms and a comparable reduction in total egg burden. This reduced worm burden and thus egg Ag load may affect the pattern of cytokine response and thereby the ability to modulate the granuloma. The relationship between the intensity of experimental infection and granuloma size has been examined in detail in different animal models of schistosomiasis (3). No consistent relationship between infection intensity and granuloma size has been found from experimental infection of rabbits or monkeys with any schistosome species or with S. mansoni infection in most murine strains. Thus, the observed differences in worm burdens between primary infection and reinfection are unlikely to account for the differences in cytokine production, antibody levels, or granuloma size. We also observed few hepatic granulomas in chronically infected animals after the primary or secondary infection. This was not related to intensity of infection, decreased egg output, or worm burdens at perfusion among the different groups. Although it is not well understood why fewer hepatic granulomas were observed in chronically infected animals, the finding may represent further migration of adults to the distal mesenteric vasculature such that fewer eggs embolize in the liver.
The present study suggests that selective-population chemotherapy for
schistosomiasis is unlikely to exacerbate host-induced acute
granulomatous responses with subsequent infection. However, the
long-term effects on fibrosis and chronic modulation remain to be fully
determined. The study also concludes that granuloma modulation was the
result of a generalized suppression of cytokine synthesis, probably by
the immunomodulatory function of TGF-. In addition, these studies
point to the value of the baboon as a model to study the
immunopathology of human schistosomiasis and provide unique insights
into its pathophysiology that may not be apparent from studies in mice.
| |
ACKNOWLEDGMENTS |
|---|
Support was provided by NIH grants AI-35935 and AI-01202.
We are indebted to J. Nyaundi, M. Njenga, and M. Suleman for surgical expertise and to Simon Kiarie, Fred Nyundo, and Sammy Kisara for excellent technical assistance. Francois Villinger kindly helped to develop and verify the baboon cytokine assays. Lynn Elson provided key help with initial infection and immunological assays. We thank Abram Stavitsky, Eric Pearlman, and Diana Martin for critical review of the manuscript.
| |
FOOTNOTES |
|---|
* Corresponding author. Mailing address: Division of Geographic Medicine, School of Medicine, Case Western Reserve University, 2109 Adelbert Rd., Cleveland, OH 44106-4983. Phone: (216) 368-4817. Fax: (216) 368-4825. E-mail: cxk21{at}po.cwru.edu.
Editor: R. N. Moore
| |
REFERENCES |
|---|
|
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
|
|---|
| 1. |
Barcy, S.,
M. Wettendorff,
O. Leo,
J. Urbain,
M. Druger,
J. Ceuppens, and M. de Boer.
1995.
FcR cross-linking on monocytes results in impaired T cell stimulatory capacity.
Int. Immunol.
7:179 |
| 2. | Boros, D. L., and N. W. Lukacs. 1992. The role of egg antigens, cytokines in granuloma formation in murine schistosomiasis mansoni. Mem. Inst. Oswaldo Cruz 87:75-79. |
| 3. | Cheever, A. W. 1986. The intensity of experimental schistosome infections modulates hepatic pathology. Am. J. Trop. Med. Hyg. 35:124-133. |
| 4. | Cheever, A. W., and Z. A. Andrade. 1967. Pathological lesions associated with Schistosoma mansoni infection in man. Trans. R. Soc. Trop. Med. Hyg. 61:626-639[Medline]. |
| 5. | Cheever, A. W., J. E. Byram, S. Hieny, F. von Lichtenberg, M. N. Lunde, and A. Sher. 1985. Immunopathology of Schistosoma japonicum and Schistosoma mansoni infection in B cell depleted mice. Parasite Immunol. 7:399-413[Medline]. |
| 6. |
Chensue, S. W.,
K. S. Warmington,
J. Ruth,
P. M. Lincoln, and S. L. Kunkel.
1994.
Cross-regulatory role of IFN-, IL-4 and IL-10 in schistosome egg granuloma formation: in vivo regulation of Th activity and inflammation.
Clin. Exp. Immunol.
98:395-400[Medline].
|
| 7. |
Chiaramonte, M. G.,
L. R. Schopf,
T. Y. Neben,
A. W. Cheever,
D. D. Donaldson, and T. A. Wynn.
1999.
IL-13 is a key regulatory cytokine for Th2 cell-mediated pulmonary granuloma formation and IgE responses induced by Schistosoma mansoni eggs.
J. Immunol.
162:920-930 |
| 8. | Coelho, P. M., N. H. Toppa, J. S. Feldmann, R. Goncalves, and R. T. Mello. 1996. Schistosoma mansoni: permanence of modulation of the granulomatous inflammatory response in mice cured in the chronic phase. Int. J. Parasitol. 26:1393-1395[Medline]. |
| 9. | Colley, D. G., A. A. Garcia, J. R. Lambertucci, J. C. Parra, N. Katz, R. S. Rocha, and G. Gazzinelli. 1986. Immune responses during human schistosomiasis. XII. Differential responsiveness in patients with hepatosplenic disease. Am. J. Trop. Med. Hyg. 35:793. |
| 10. | Domingo, E. O., and K. S. Warren. 1968. Endogenous desensitization: changing host granulomatous response to schistosome eggs at different stages of infection with schistosoma mansoni. Am. J. Pathol. 52:369-379[Medline]. |
| 11. | Ellner, J. J., G. R. Olds, E. S. Osman, A. El Kholy, and A. A. F. Mahmoud. 1981. Dichotomies in the reactivity to worm Ag in human schistosomiasis mansoni. J. Immunol. 126:309[Abstract]. |
| 12. | Farah, I. O., and M. Nyindo. 1996. Schistosoma mansoni induces in the Kenyan baboon a novel intestinal pathology that is manifestly modulated by an irradiated cercarial vaccine. J. Parasitol. 82:601-607[Medline]. |
| 13. | Farah, I. O., M. Nyindo, M. A. Suleman, J. Nyaundi, T. M. Kariuki, R. E. Blanton, L. H. Elson, and C. L. King. 1997. Schistosoma mansoni: development and modulation of the granuloma after single or multiple exposures in the baboon (Papio cynocephalus anubis). Exp. Parasitol. 86:93-101[Medline]. |
| 14. | Grogan, J. L., P. G. Kremsner, J. G. van Dam, W. Metzger, B. Mordmuller, A. Deelder, and M. Yazdanbakhsh. 1996. Antischistosome IgG4 and IgE responses are affected differentially by chemotherapy in children versus adults. J. Infect. Dis. 173:1242-1247[Medline]. |
| 15. | Grogan, J. L., P. G. Kremsner, A. M. Deelder, and M. Yazdanbakhsh. 1996. Elevated proliferation and interleukin-4 release from CD4+ cells after chemotherapy in human Schistosoma haematobium infection. Eur. J. Immunol. 26:1365-1370[Medline]. |
| 16. | Grogan, J. L., P. G. Kremsner, A. M. Deelder, and M. Yazdanbakhsh. 1998. Antigen-specific proliferation and interferon-gamma and interleukin-5 production are down-regulated during Schistosoma haematobium infection. J. Infect. Dis. 177:1433-1437[Medline]. |
| 17. | Grogan, J. L., P. G. Kremsner, A. M. Deelder, and M. Yazdanbakhsh. 1998. The effect of anti-IL-10 on proliferation and cytokine production in human schistosomiasis: fresh versus cryopreserved cells. Parasite Immunol. 20:345-349[Medline]. |
| 18. |
Jankovic, D.,
A. W. Cheever,
M. C. Kullberg,
T. A. Wynn,
G. Yap,
P. Caspar,
F. A. Lewis,
R. Clynes,
J. V. Ravetch, and A. Sher.
1998.
CD4+ T cell-mediated granulomatous pathology in schistosomiasis is downregulated by a B cell-dependent mechanism requiring Fc receptor signaling.
J. Exp. Med.
187:619-629 |
| 19. | Jankovic, D., M. C. Kullberg, D. Dombrowicz, S. Barbieri, P. Caspar, T. A. Wynn, W. E. Paul, A. W. Cheever, J. P. Kinet, and A. Sher. 1997. Fc epsilonRI-deficient mice infected with Schistosoma mansoni mount normal Th2-type responses while displaying enhanced liver pathology. J. Immunol. 159:1868-1875[Abstract]. |
| 20. | King, C. L., A. Medhat, I. Malhotra, M. Nafeh, A. Helmy, J. Khaudary, S. Ibrahim, M. El-Sherbiny, S. Zaky, R. J. Stupi, K. Brustoski, M. Shehata, and M. T. Shata. 1996. Cytokine control of parasite-specific anergy in human urinary schistosomiasis. IL-10 modulates lymphocyte reactivity. J. Immunol. 156:4715-4721[Abstract]. |
| 21. |
Letterio, J. J., and A. B. Roberts.
1998.
Regulation of immune responses by TGF-.
Annu. Rev. Immunol.
16:137-161[Medline].
|
| 22. | Li, Z., C. L. King, J. O. Ogundipe, L. S. Licate, and R. E. Blanton. 1995. Preferential recognition by human IgE and IgG4 of a species-specific Schistosoma haematobium serine protease inhibitor. J. Infect. Dis. 171:416-422[Medline]. |
| 23. | Lukacs, N. W., and D. L. Boros. 1993. Lymphokine regulation of granuloma formation in murine schistosomiasis mansoni. Clin. Immunol. Immunopathol. 68:57-63[Medline]. |
| 24. | Mahanty, S., C. L. King, V. Kumaraswami, J. Regunathan, A. Maya, K. Jayaraman, J. S. Abrams, E. A. Ottesen, and T. B. Nutman. 1993. IL-4- and IL-5-secreting lymphocyte populations are preferentially stimulated by parasite-derived antigens in human tissue invasive nematode infections. J. Immunol. 151:3704-3711[Abstract]. |
| 25. | Medhat, A., M. Shehata, K. Bucci, S. Mohamed, A. Diab, S. Badary, H. Galal, M. Nafeh, and C. L. King. 1998. Increased interleukin-4 and interleukin-5 production in response to Schistosoma haematobium adult worm antigens correlates with lack of re-infection after treatment. J. Infect. Dis. 178:512-519[Medline]. |
| 26. |
Montesano, M. A.,
D. G. Colley,
S. Eloi-Santos,
G. L. Freeman, and W. E. Secor.
1999.
Neonatal idiotypic exposure alters subsequent cytokine, pathology, and survival patterns in experimental Schistosoma mansoni infections.
J. Exp. Med.
189:637-645 |
| 27. | Moskophidis, D., F. Lechner, H. Pircher, and R. M. Zinkernagel. 1993. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature 362:758-761[Medline]. |
| 28. | Mutapi, F., P. D. Ndhlovu, P. Hagan, J. T. Spicer, T. Mduluza, C. M. Turner, S. K. Chandiwana, and M. E. Woolhouse. 1998. Chemotherapy accelerates the development of acquired immune responses to Schistosoma haematobium infection. J. Infect. Dis. 178:289-293[Medline]. |
| 29. |
Mwatha, J. K.,
G. Kimani,
T. Kamau,
G. G. Mbugua,
J. H. Ouma,
J. Mumo,
A. J. Fulford,
F. M. Jones,
A. E. Butterworth,
M. B. Roberts, and D. W. Dunne.
1998.
High levels of TNF, soluble TNF receptors, soluble ICAM-1, and IFN-gamma, but low levels of IL-5, are associated with hepatosplenic disease in human schistosomiasis mansoni.
J. Immunol.
160:1992-1999 |
| 30. | Newport, G. R., and D. G. Colley. 1993. Schistosomiasis, p. 387. In K. S. Warren (ed.), Immunology and molecular biology of parasitic infections. Blackwell Scientific Publications, Oxford, United Kingdom. |
| 31. |
Nyindo, M.,
T. Kariuki,
P. Mola,
I. Farah,
L. Elson,
R. E. Blanton, and C. L. King.
1999.
Role of adult worm antigen-specific immunoglobulin E in acquired immunity to Schistosoma mansoni infection in baboons.
Infect. Immun.
67:636-642 |
| 32. | Olveda, R. M., B. L. Daniel, B. D. Ramirez, G. D. Aligui, L. P. Acosta, P. Fevidal, E. Tiu, F. de Veyra, P. A. Peters, R. Romulo, E. Domingo, P. M. Wiest, and G. R. Olds. 1996. Schistosomiasis japonica in the Philippines: the long-term impact of population-based chemotherapy on infection, transmission, and morbidity. J. Infect. Dis. 174:163-172[Medline]. |
| 33. |
Pearce, E. J.,
P. Caspar,
J. M. Grzych,
F. A. Lewis, and A. Sher.
1991.
Downregulation of Th1 cytokine production accompanies induction of Th2 responses by a parasitic helminth, Schistosoma mansoni.
J. Exp. Med.
173:159-166 |
| 34. |
Roberts, M.,
A. E. Butterworth,
G. Kimani,
T. Kamau,
A. J. Fulford,
D. W. Dunne,
J. H. Ouma, and R. F. Sturrock.
1993.
Immunity after treatment of human schistosomiasis: association between cellular responses and resistance to reinfection.
Infect. Immun.
61:4984-4993 |
| 35. |
Rumbley, C. A.,
S. A. Zekavat,
H. Sugaya,
P. J. Perrin,
M. A. Ramadan, and S. M. Phillips.
1998.
The schistosome granuloma: characterization of lymphocyte migration, activation, and cytokine production.
J. Immunol.
161:4129-4137 |
| 36. | Shaker, Z., H. Hassanein, M. Kamel, N. El-Bahairy, A. El-Kalouby, and E. El-Raziky. 1987. Effect of praziquantel on certain immune responses of schistosomal Egyptian patients. I. Changes of specific immunoglobulins. Parasitol. Res. 73:328-333[Medline]. |
| 37. |
Starzl, T. E., and R. M. Zinkernagel.
1998.
Antigen localization and migration in immunity and tolerance.
N. Engl. J. Med.
339:1905-1913 |
| 38. | Sturrock, R. F., A. E. Butterworth, and V. Houba. 1976. Schistosoma mansoni in the baboon (Papio anubis): parasitological responses of Kenyan baboons to different exposures of a local parasite strain. Parasitology 73:239-252[Medline]. |
| 39. | Subramanian, A., P. Mungai, J. Ouma, P. Magak, C. H. King, A. F. Mahmoud, and C. L. King. 1999. Long-term suppression of adult bladder morbidity and severe hydronephrosis following selective population chemotherapy for Schistosoma haematobium. Am. J. Trop. Med. Hyg. 61:476-481[Abstract]. |
| 40. |
Todd, C. W.,
R. W. Goodgame, and D. G. Colley.
1979.
Immune responses during human schistosomiasis mansoni. V. Suppression of schistosome antigen-specific lymphocyte blastogenesis by adherent/phagocytic cells.
J. Immunol.
122:1440-1446 |
| 41. | Viana, I. R., A. Sher, O. S. Carvalho, C. L. Massara, S. M. Eloi-Santos, E. J. Pearce, D. G. Colley, G. Gazzinelli, and R. Correa-Oliveira. 1994. Interferon-gamma production by peripheral blood mononuclear cells from residents of an area endemic for Schistosoma mansoni. Trans. R. Soc. Trop. Med. Hyg. 88:466-470[Medline]. |
| 42. | Villinger, F., S. S. Brar, A. Mayne, N. Chikkala, and A. A. Ansari. 1995. Comparative sequence analysis of cytokine genes from human and nonhuman primates. J. Immunol. 155:3946-3954[Abstract]. |
| 43. | Virgin, H. W. T., G. F. Wittenberg, and E. R. Unanue. 1985. Immune complex effects on murine macrophages. I. Immune complexes suppress interferon-gamma induction of Ia expression. J. Immunol. 135:3735-3743[Abstract]. |
| 44. | Weiner, H. L., A. Friedman, A. Miller, S. J. Khoury, A. al-Sabbagh, L. Santos, M. Sayegh, R. B. Nussenblatt, D. E. Trentham, and D. A. Hafler. 1994. Oral tolerance: immunologic mechanisms and treatment of animal and human organ-specific autoimmune diseases by oral administration of autoantigens. Annu. Rev. Immunol. 12:809-837[Medline]. |
| 45. | Williams, M. E., S. Montenegro, A. L. Domingues, T. A. Wynn, K. Teixeira, S. Mahanty, A. Coutinho, and A. Sher. 1994. Leukocytes of patients with Schistosoma mansoni respond with a Th2 pattern of cytokine production to mitogen or egg antigens but with a Th0 pattern to worm antigens. J. Infect. Dis. 170:946-954[Medline]. |
| 46. |
Wynn, T. A.,
A. W. Cheever,
M. E. Williams,
S. Hieny,
P. Caspar,
R. Kuhn,
W. Muller, and A. Sher.
1998.
IL-10 regulates liver pathology in acute murine Schistosomiasis mansoni but is not required for immune down-modulation of chronic disease.
J. Immunol.
160:4473-4480 |
| 47. | Yamashita, T., and D. L. Boros. 1992. IL-4 influences IL-2 production and granulomatous inflammation in murine schistosomiasis mansoni. J. Immunol. 149:3659-3664[Abstract]. |
| 48. | Zwingenberger, K., E. Irschick, J. G. S. Vergetti, A. R. C. Decal, R. Janssen-Rosseck, U. Bienzle, C. Huber, and H. Feldmeier. 1989. Release of interleukin-2 and gamma interferon by peripheral mononuclear cells in human Schistosomiasis mansoni infection normalizes after chemotherapy. Scand. J. Immunol. 30:463-471[Medline]. |
Infection and Immunity, December 1999, p. 6565-6571, Vol. 67, No. 12
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
This article has been cited by other articles:
-
Martins-Leite, P., Gazzinelli, G., Alves-Oliveira, L. F., Gazzinelli, A., Malaquias, L. C. C., Correa-Oliveira, R., Teixeira-Carvalho, A., Silveira, A. M. S.
(2008). Effect of Chemotherapy with Praziquantel on the Production of Cytokines and Morbidity Associated with Schistosomiasis Mansoni. Antimicrob. Agents Chemother.
52: 2780-2786
[Abstract] [Full Text] -
Heninger, E., Hogan, L. H., Karman, J., Macvilay, S., Hill, B., Woods, J. P., Sandor, M.
(2006). Characterization of the Histoplasma capsulatum-Induced Granuloma.. J. Immunol.
177: 3303-3313
[Abstract] [Full Text] -
Leng, Q., Bentwich, Z., Borkow, G.
(2006). Increased TGF-{beta}, Cbl-b and CTLA-4 levels and immunosuppression in association with chronic immune activation. Int Immunol
18: 637-644
[Abstract] [Full Text] -
Borkow, G., Bentwich, Z.
(2004). Chronic Immune Activation Associated with Chronic Helminthic and Human Immunodeficiency Virus Infections: Role of Hyporesponsiveness and Anergy. Clin. Microbiol. Rev.
17: 1012-1030
[Abstract] [Full Text] -
Kaviratne, M., Hesse, M., Leusink, M., Cheever, A. W., Davies, S. J., McKerrow, J. H., Wakefield, L. M., Letterio, J. J., Wynn, T. A.
(2004). IL-13 Activates a Mechanism of Tissue Fibrosis That Is Completely TGF-{beta} Independent. J. Immunol.
173: 4020-4029
[Abstract] [Full Text] -
Kariuki, T. M., Farah, I. O., Yole, D. S., Mwenda, J. M., Van Dam, G. J., Deelder, A. M., Wilson, R. A., Coulson, P. S.
(2004). Parameters of the Attenuated Schistosome Vaccine Evaluated in the Olive Baboon. Infect. Immun.
72: 5526-5529
[Abstract] [Full Text] -
Stavitsky, A. B.
(2004). Regulation of Granulomatous Inflammation in Experimental Models of Schistosomiasis. Infect. Immun.
72: 1-12
[Full Text] -
Hefty, P. S., Brooks, C. S., Jett, A. M., White, G. L., Wikel, S. K., Kennedy, R. C., Akins, D. R.
(2002). OspE-Related, OspF-Related, and Elp Lipoproteins Are Immunogenic in Baboons Experimentally Infected with Borrelia burgdorferi and in Human Lyme Disease Patients. J. Clin. Microbiol.
40: 4256-4265
[Abstract] [Full Text] -
Farah, I. O., Mola, P. W., Kariuki, T. M., Nyindo, M., Blanton, R. E., King, C. L.
(2000). Repeated Exposure Induces Periportal Fibrosis in Schistosoma mansoni-Infected Baboons: Role of TGF-{beta} and IL-4. J. Immunol.
164: 5337-5343
[Abstract] [Full Text] -
Montesano, M. A., Colley, D. G., Willard, M. T., Freeman, G. L. Jr., Secor, W. E.
(2002). Idiotypes Expressed Early in Experimental Schistosoma mansoni Infections Predict Clinical Outcomes of Chronic Disease. JEM
195: 1223-1228
[Abstract] [Full Text]
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Copyright © 2009 by the American Society for Microbiology. For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»