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*
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115;
Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI 48201; and
Department of Medicine, Harvard Medical School, Boston, MA 02115
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and
Ag-specific IgG2a and IgG2b following schistosome egg injection. This
shift away from a Th2 cell-mediated immune response was coupled with
the development of pulmonary and hepatic granulomas that were greatly
decreased in size compared with those in control littermates. Hepatic
granulomas in Stat6-deficient mice were composed of predominantly
mononuclear cells with very sparse appearance of eosinophils, and their
diminished size was accompanied by decreased amounts of liver
hydroxyproline content as a measure of collagen deposition. In
contrast, lymphocytes from infected Stat4-deficient mice produced Th2
cell cytokines in amounts comparable to those produced by control
littermates, but low levels of IFN-. While infected Stat4-deficient
mice developed pulmonary granulomas following schistosome egg injection
that were modestly impaired in size, the granuloma size and amount of
collagen deposition in the liver were equivalent to those seen in
control littermates. These studies demonstrate that Th2 cells are
required for the full development of the granulomas and
tissue-destructive fibrotic pathology associated with the immune
response to S. mansoni ova. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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expression was also observed in many of these studies,
consistent with early experiments suggesting that granuloma formation
in S. mansoni-infected mice is the consequence of a
delayed-type hypersensitivity reaction (15). Administration of IL-4
with schistosome eggs led to increased granuloma size, while
anti-IL-4 suppressed granuloma formation and hepatic fibrosis
(16, 17, 18, 19, 20). Moreover, infection of IL-4-deficient mice on a C57BL/6
background led to the development of smaller hepatic granulomas than
those seen in control mice (3), although there was less of an effect on
granuloma size seen in IL-4-deficient mice on a mixed genetic
background (21). Abs to other Th2 cytokines, such as IL-5 or IL-10, had
little effect, leading to only slightly altered size or cellular
composition of the granuloma (18, 22). Finally, administration of IL-12
to schistosome egg-injected mice, which promotes a Th1 response while
inhibiting Th2 cell function, led to an impaired granulomatous response
(23, 24). Similarly, elimination of IFN-, which leads to
up-regulation of Th2 cell function, led to increased granuloma size
(17, 23, 25). Cumulatively, these results suggest that the development
of schistosome egg-induced granulomas is a complex process and that
both Th1 and Th2 cell subsets may play important roles in regulating
granuloma formation. We have recently generated Stat4- and Stat6-deficient mice, which have defects in the signal transduction pathways that affect the development of Th1 and Th2 cells, respectively (26, 27). To determine more clearly the dependence on Th1 and Th2 cells of the schistosome egg-induced granulomatous response, we have examined the immune response to S. mansoni ova in these gene-targeted mice. We demonstrate that schistosome egg injection of naive or infected Stat6-deficient mice leads to greatly decreased pulmonary and hepatic granuloma size and collagen deposition, correlating with the absence of a Th2 cell response. Moreover, the soluble egg Ag (SEA)3-specific response in these mice has all the hallmarks of a vigorous Th1 cell response. In contrast, Stat4-deficient mice, which have impaired Th1 cell responses, develop schistosome egg-induced granulomatous responses in the lung that are only modestly diminished compared with those in control mice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Stat4- and Stat6-deficient mice have previously been described (26, 27). Homozygous Stat4- and Stat6-deficient mice and their wild-type control littermates were of a mixed BALB/c x 129/Sv genetic background and were used at 8 to 12 wk of age. Animals were bred in the facilities of the Harvard School of Public Health under specific pathogen-free conditions and were transferred to Wayne State University (Detroit, MI) for infection.
Schistosome eggs were obtained from autolyzed homogenized livers of mice infected with 200 cercariae of the Puerto Rican strain of S. mansoni. Naive mice were injected with 2500 schistosome eggs via the tail vein. In some experiments, mice were infected by s.c. injection of 25 schistosome cercariae. Seven weeks after infection, mice were injected with 2500 schistosome eggs via the tail vein. Animals were killed and analyzed either 17 days (naive mice) or 8 days (infected mice) following schistosome egg injection. No mortality or morbidity expressed by weight loss were observed. SEA was obtained from homogenized schistosome eggs as previously described (15).
Cytokine production and analysis
Spleens, mesenteric lymph nodes (MLN), and livers were removed from infected mice aseptically. Erythrocytes were lysed from dispersed spleen cell suspensions by hypotonic shock. Hepatic granulomas were obtained by gentle homogenization of livers from infected mice. Granuloma cells were obtained by treatment of granulomas with 0.2% type IV collagenase (Sigma Chemical Co., St. Louis, MO) and mechanical disruption as previously described (28).
Spleen, MLN, and granuloma cells were suspended at a concentration of
3 x 106/ml in RPMI 1640 medium supplemented with
10% FCS, 2 x 10-5 M 2-ME, 20 mM HEPES, 2 mM sodium
pyruvate, 1 mM glutamine, 100 U/ml penicillin, and 100 µg/ml
streptomycin. An aliquot of 0.5 ml of cells was cultured in 48-well
plates in the presence of 10 µg/ml of SEA. Before culture, granuloma
cells were preincubated at 37°C on plastic culture plates to remove
adherent macrophages. For each experiment, cell cultures were prepared
from a pool of at least four mice. Supernatants from cell cultures were
harvested at 18 to 24 h for IL-2 and IL-4 quantitation or at
48 h for analysis of IFN-, IL-5, and IL-10.
Levels of secreted IL-2 were determined with the IL-2-dependent cell
line CTLL-20 provided by Dr. F. Fitch, and IL-4 was assayed using the
IL-4-dependent cell line CT4S provided by Dr. W. Paul. The assays were
conducted as described previously (29). The specificity of the assays
was verified by the use of anti-IL-2 and anti-IL-4 mAbs in both
the CTLL-20 and CT4S cultures. IL-5, IL-10, and IFN- levels were
measured with Ab pairs (PharMingen, San Diego, CA) by the sandwich
ELISA assay. Biotinylated detecting Ab was labeled with Streptavidin
(Life Technologies, Gaithersburg, MD) alkaline phosphatase, and the
assay was developed with p-nitrophenyl phosphate substrate
(Sigma).
Ab analysis
Total Ig levels were analyzed by sandwich ELISA using isotype-specific capture and alkaline phosphatase-labeled detection Abs (Southern Biotechnology, Birmingham, AL). IgE-specific Ig and standards were purchased from PharMingen.
Ag-specific antibody titers were determined by adding serial dilutions of sera to plates coated with 5 µg/ml SEA. Individual isotypes were detected as described above. Specific titers were derived by averaging the product of the optical density and the reciprocal of the dilution from two points in the linear portion of the dilution curve.
Hydroxyproline assay
Hydroxyproline content as a measure of collagen production was assayed in acid-hydrolyzed liver samples as previously described (30).
Granuloma measurement
Lungs were filled with buffered formalin and processed for histology. Hepatic and pulmonary granulomas were measured in 5-µm-thick hematoxylin-eosin-stained tissue sections. Coded slides were examined in a blinded fashion by means of computerized morphometry using the Microcomp Image Analysis Program (Southern Micro Instruments, Atlanta, GA). The significance of the results was evaluated by Student’s t test.
Granuloma eosinophil count
Paraffin-embedded livers were sectioned at 5-µm thickness and stained by the modified Dominici stain (31). Toluidine blue O was used as counterstain. Granuloma eosinophils were counted under immersion oil at x1000 magnification. Eosinophils were counted in four fields from each granuloma, and 17 granulomas were examined for each mouse.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The correlation between the development of schistosome egg-induced
granulomas and the presence of Th2 cells in the granuloma itself led us
to determine the importance of Th2 cells in the granulomatous response.
Initially, we analyzed both cytokine production and pulmonary granuloma
formation 17 days after i.v. injection of 2500 S. mansoni
ova into naive mice. Spleen cells from schistosome egg-injected control
and Stat6-deficient mice produced high levels of the Th1 cell cytokines
IFN- (p < 0.05 for Stat6-deficient vs
control cells) and IL-2 (Fig. 1
and data
not shown) following in vitro stimulation with SEA. While stimulation
of spleen cells from control mice also led to the production of Th2
cell cytokines such as IL-4, IL-5, and IL-10, cells from
Stat6-deficient mice produced minimal IL-4 and greatly reduced levels
of IL-5 and IL-10, consistent with a lack of Th2 cell generation in
vivo. Histologic examination of granuloma development in the lung
showed that, in contrast to control mice, Stat6-deficient mice had very
small granulomas. Computerized morphometry of the granuloma area
revealed that pulmonary granulomas induced in Stat6-deficient mice were
13% the size of those in control mice (p <
0.001; Fig. 2). These results suggest a
crucial role for Th2 cells in the development of pulmonary granulomas
in response to schistosome eggs.
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To further address the role of Th2 cells in the immune response to
S. mansoni ova, we infected mice with 25 S.
mansoni cercariae. Seven weeks after infection, mice were injected
i.v. with 2500 schistosome eggs, and 8 days later, mice were killed and
analyzed for cytokine production, Ab titers, pulmonary and hepatic
granuloma size, and liver hydroxyproline content as a measure of
collagen deposition. Similar to that seen for schistosome egg-injected
naive mice, spleen and MLN cells from infected control, but not
Stat6-deficient, mice produced high levels of Th2 cell cytokines
following in vitro stimulation with SEA (Fig. 3). Consistent with their skewing toward
a Th1 cell phenotype, spleen cells from Stat6-deficient mice secreted
15-fold more IFN- than cells from control mice when stimulated with
SEA in vitro. Some differences in the cytokine secretion profiles of
spleen vs MLN cells in infected mice were observed, and this may
reflect differences in cell populations or cell trafficking to and from
the organs. Cells from control and Stat6-deficient mice secreted
equivalent levels of IL-2 (data not shown).
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A). There was a marked
increase in IgG2a in Stat6-deficient mice (9-fold over the control
value) with more modest trends toward increases in IgG2b and IgG3
levels. Sera were also tested for the presence of SEA-specific Abs.
Control mice generated an Ag-specific antibody response that was
comprised predominantly of IgG1 and IgG3 isotypes with modest levels of
IgE (Fig. 4B). The profile in Stat6-deficient mice
was strikingly different. While there was Ag-specific IgG1, titers were
decreased to 20% of those seen in control mice. In contrast, there
were 130- and 80-fold increases in the levels of Ag-specific IgG2a and
IgG2b, respectively, over those in control mice. IgG3 levels were
within the range of control mice, and as expected, Ag-specific IgE was
undetectable in serum from Stat6-deficient mice. The appearance of
particular cytokines (Fig. 3
) and isotypes of Abs (Fig. 4) in infected
Stat6-deficient mice strongly suggests the generation of an
SEA-specific Th1 cell-mediated immune response to S.
mansoni ova.
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, A and
B). Observations of stained sections under oil
immersion revealed that hepatic granulomas in infected Stat6-deficient
mice were composed of predominantly mononuclear cells, with very sparse
appearance of eosinophils. The mean eosinophil count per hepatic
granuloma ± SE of three mice was 46.8 ± 3.8 in control mice
vs 3.9 ± 0.6 in Stat6-deficient mice. Additionally, the amount of
collagen deposition within the liver, assessed by measurement of
hydroxyproline levels, was also greatly decreased in Stat6-deficient
mice (Fig. 5C). In vitro analysis of granuloma cells
from Stat6-deficient mice was not possible because the small granulomas
present were dispersed during the homogenization of liver tissue. Taken
together, these data provide further evidence that in the absence of a
Th2 response, the tissue-destructive fibrotic pathology associated with
the S. mansoni ova-induced granulomatous response is greatly
diminished.
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In addition to the extensive evidence supporting a central role of
Th2 cells in the schistosome egg-induced granulomatous response,
several studies have also suggested a role for Th0/Th1 cells (9, 12, 29, 34). To address the importance of Th1 cells in the immune response
to S. mansoni, we infected control and Stat4-deficient mice
with 25 S. mansoni cercariae. Seven weeks after infection,
mice were injected i.v. with 2500 schistosome eggs, and 8 days later,
mice were killed and analyzed for cytokine production, Ab titers,
pulmonary and hepatic granuloma size, and liver hydroxyproline content
as a measure of collagen deposition. Cytokine production from spleen
and MLN cells following in vitro stimulation with SEA is shown in
Figure 6. Similar amounts of Th2 cell
cytokines were produced by cultures of control and Stat4-deficient
cells. In contrast, Stat4-deficient cells produced greatly decreased
levels of IFN-, consistent with their inability to
differentiate into Th1 cells as previously seen in vitro
(27, 35).
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A).
This difference was even more dramatic upon examination of SEA-specific
Ab titers, where there was a 300-fold decrease in the levels of
SEA-specific IgG3 (Fig. 7B). The development of Th2
cell-mediated IgG1 and IgE responses was normal in
Stat4-deficient mice.
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A). The sizes of the
granulomas formed in the lung were decreased by 22% in Stat4-deficient
mice compared with those in control mice (p <
0.001). Interestingly, the sizes of hepatic granulomas in
Stat4-deficient mice were not significantly different from those in
control mice (Fig. 8B) even though there was a 30%
decrease in eosinophil content. The mean eosinophil count per hepatic
granuloma ± SE of three mice was 52.9 ± 3.9 in control mice
vs 37.8 ± 3.2 in Stat4-deficient mice. Furthermore, the level of
collagen deposition in the liver, as assayed by hydroxyproline content,
was similar in infected control and Stat4-deficient mice (Fig. 8C). In vitro stimulation of hepatic granuloma cells
from Stat4-deficient mice with SEA led to greatly diminished levels of
IFN- compared with those in cells from control mice, while the
amounts of Th2 cell cytokines produced in these cultures were similar
(Fig. 9). Thus, while the lack of Stat4
leads to decreased levels of Th1 cell cytokine production and an
altered Ab response, there is only a modest effect on the development
of pulmonary granulomas in response to schistosome eggs.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In this report, we demonstrate that in the absence of Th2 cell function, the development of egg-induced granulomas in the lung and liver is severely impaired during schistosome infection. The decrease in granuloma size was more pronounced in pulmonary granulomas in naive animals than in hepatic granulomas from infected mice, indicating the higher sensitivity of the synchronous pulmonary granulomatous response. This contrast could be due either to organ-related differences (36) and/or to the strength of the antigenic stimulus provided by previously incubated and injected vs freshly laid eggs (20). Our results are in agreement with several reports demonstrating the importance of Th2 cell responses for both hepatic granuloma formation and fibrosis (16, 17, 18, 19, 20, 37) as well as for the survival of the infected host (38). In addition, our observations are similar to two recent reports examining schistosome infection in IL-4-deficient mice. Pearce et al. saw modest decreases in pulmonary, but not hepatic, granuloma size in IL-4-deficient mice on a mixed genetic background (21), while schistosome infection of IL-4-deficient mice on a pure C57BL/6 background led to a significant decrease in hepatic granuloma size (3). The profound diminution in granuloma size seen in infected Stat6-deficient mice compared with that in control littermates may in part be attributable to a reduction in the number of intragranulomatous eosinophils. This observation correlates with the low level of IL-5 production by Stat6-deficient cells. Importantly, the development of smaller granulomas in Stat6-deficient mice was coupled with a significant decrease in the deposition of collagen, which may also be a consequence of the lack of Th2 cell function. Murine fibroblasts have been shown to possess IL-4R and to synthesize collagen after IL-4 stimulation (39). While this function of IL-4 has not been demonstrated to be Stat6 dependent, it is possible that the impaired collagen deposition seen in infected Stat6-deficient mice results from both the deficiency in IL-4-producing T cells and from the inability of the fibroblasts to respond to IL-4. Moreover, it is possible that Stat6 plays additional roles outside the immune system. Stat6 is widely expressed and can transmit signals for other cytokines, such as platelet-derived growth factor (40), which may also be important in fibrosis or cellular recruitment to the granuloma. Additional studies will be necessary to examine these possibilities.
In the absence of Th2 cells, the granulomas that developed in infected
Stat6-deficient mice were composed predominantly of mononuclear cells.
Moreover, there was an increase in the amount of SEA-specific IgG2a and
IgG2b, and spleen cells produced higher levels of IFN- following
stimulation with SEA in vitro. This phenotype was not seen in
schistosome-infected IL-4-deficient mice (3) and may be due to the
actions of other cytokines, such as IL-13, which can function in
IL-4-deficient, but not Stat6-deficient, mice. Taken together, however,
our results suggest that in the absence of Stat6, an SEA-specific Th1
response developed. The small granulomas observed in Stat6-deficient
mice could be regulated by a number of factors, including TNF-
,
which has been shown to have a role in granuloma formation (41, 42).
The expression of this cytokine is not restricted to either Th cell
subset, so Th1 or Th2 cells could contribute to TNF--directed
granuloma development. Additionally, both monocyte chemoattractant
protein-1 and macrophage inflammatory protein-1 have been shown to
modulate the size of schistosome egg-induced granulomas (43, 44),
although some of this function could be due to skewing of Th cell
subsets (45). The roles of these other factors in regulating the
development of granulomas will be the focus of future
investigation.
As expected, spleen, MLN, and granuloma cells of Stat4-deficient mice
produced normal amounts of IL-4, IL-5, and IL-10 and negligible levels
of IFN- following infection with S. mansoni. Despite the
apparently normal Th2 cell function, pulmonary granuloma formation was
modestly inhibited in infected Stat4-deficient mice. This was somewhat
surprising given that previous studies demonstrated larger granulomas
in the absence of Th1 cell-mediated regulation (17, 18, 24). Thus,
while granuloma formation may not be absolutely dependent on Th1 cells,
it is likely they still play a regulatory role in the schistosome
egg-induced granulomatous response. In conclusion, our results
demonstrate that Th2 cells are critical for the full development of
schistosome egg-induced granulomas. In the absence of Th2 cells,
alternative pathways, possibly regulated by Th1 cells, lead to the
formation of a reduced granuloma. Future studies will be aimed at
elucidating the inflammatory molecules involved in the generation of
Th2 cell-independent granulomas.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Michael J. Grusby, Department of Immunology and Infectious Diseases, Harvard School of Public Health, 651 Huntington Ave., Boston, MA 02115. E-mail address:
3 Abbreviations used in this paper: SEA, soluble egg Ag; MLN, mesenteric lymph nodes.
Received for publication September 12, 1997. Accepted for publication October 29, 1997.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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