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*
Laboratory for Infection and Immunity,
Department of Medical Microbiology, and
Department of Pathology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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production, weaker delayed hypersensitivity (DTH),
and slower organism clearance following chlamydial infection in mice.
To assess more directly the role of IL-10, we examined protective
immunity and pathological reaction in C57BL/6 IL-10 gene knockout (KO)
and wild-type mice. The results showed that in the absence of
endogenous IL-10, mice had significantly accelerated chlamydial
clearance and developed significantly stronger DTH responses, which
could be inhibited by local delivery of rIL-10. Consistent with the
enhancement of DTH responses, IL-10 KO mice showed stronger and more
persistent CD4 T cell-dependent IFN- production and significant
elevation of IL-12 and TNF-
production. Additionally, wild-type, but
not IL-10 KO, mice showed granuloma formation that was correlated with
higher levels of Th2 cytokine (IL-5) production at the later stages of
infection. Moreover, chlamydial infection, unlike parasitic protozoan
infection, did not induce significant acute toxicity in IL-10 KO mice,
which may be due to the low (undetectable) levels of systemic release
of proinflammatory cytokines. These results suggest that IL-10 inhibits
the priming and expansion of Th1-like T cell responses and that IL-10
plays a role in the fibrotic reaction seen with chlamydial
infection. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production in Th1 CD4 T clones and mixed spleen cells (7, 8, 9, 10). This
suppression is correlated with the inhibitory effect of IL-10 on
cytokine production and costimulatory molecule expression on APCs.
IL-10 has also been shown to inhibit the antimicrobial activity of
macrophages, possibly through altering TNF- production (11, 12, 13). The
recent development of IL-10 knockout
(KO)3 mice has provided a
powerful tool for studying the role of IL-10 in vivo (14, 15). Several
studies using various protozoan infection models have shown that IL-10
plays an important role in balancing the protective and pathological
immune responses during intracellular parasitic infection (16, 17, 18). In
particular, these studies have demonstrated that while IL-10 inhibits
protective immune responses to parasitic infection, the absence of
endogenous IL-10 due to targeted gene disruption paradoxically results
in lethal pathological reactions, characterized by systemic
overproduction of proinflammatory cytokines. To date, however, no data
are available regarding the alteration of protective and pathological
immune responses to intracellular bacterial infection in IL-10 KO mice.
Chlamydia trachomatis is an obligate intracellular bacterium
that causes a variety of human and animal diseases, affecting
principally mucosal epithelial surfaces in the eye and genital tract.
Persistent or multiple reinfection that induces immunopathological
reactions sometimes results in chronic inflammation with dense
lymphocytic and plasma cell infiltration, occasional granuloma
formation, and fibrotic scarring of the mucosa, ultimately leading to
blindness and fallopian tubal obstruction (19, 20, 21). Recent studies in
both the mouse and human have shown that IFN- production and
Th1-like T cell responses, including delayed-type hypersensitivity
(DTH), are highly correlated with host resistance to chlamydial
infection (20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33). Paradoxically, immunopathological responses
(mucosal scarring) are also thought to be mediated by DTH responses, as
suggested by studies using local delivery of soluble chlamydial Ags in
guinea pig and monkey models (34, 35).
Using a murine model of C. trachomatis mouse pneumonitis
(MoPn) lung infection, we recently found that differences in IL-10
production following chlamydial infection among inbred mouse strains
were correlated with differences in the types of immune response and
the rate of organism clearance in vivo (24, 33). Specifically, BALB/c
mice that showed higher Ab (IgG1) responses and greater susceptible to
chlamydial infection produced significantly higher levels of IL-10 than
did C57BL/6 mice. The latter mounted stronger DTH responses, had higher
IFN- production, and were more resistant to the infection. The data
suggest that IL-10 inhibits host clearance of chlamydial infection and
that IL-10 plays a negative regulatory role in the immune responses to
chlamydial infection. To more directly assess the effect of IL-10 in
immunity and immunopathologic responses to chlamydia, we examined
organism clearance and histopathology in C57BL/6 IL-10 KO mice. We also
examined the immune responses and cytokine production in IL-10 KO mice
during chlamydial infection and tested the effect of supplemental
exogenous rIL-10 on the immune responses and cytokine production in the
gene-targeted mice. Our data show that IL-10 KO mice mount strong and
persistent Th1-like T cell responses (IFN- production and DTH) and
produce significantly lower Th2-like (IL-5) cytokine. The alteration of
immune responses and cytokine patterns was correlated with a faster
clearance of organisms and the absence of granuloma formation following
chlamydial infection. Moreover, chlamydial infection, unlike parasitic
protozoan infection, did not induce significant acute toxicity in the
absence of endogenous IL-10.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female homozygous IL-10 KO mice (IL-10-/-; C57BL/6-Il10tm1Cgn) were purchased from The Jackson Laboratories (Bar Harbor, ME). Age- and sex-matched wild-type C57BL/6 mice were purchased from Charles River Canada (St. Constant, Canada). Animals were maintained in the central animal facilities of the University of Manitoba (Manitoba, Canada). IL-10 KO mice were kept in a specific pathogen-free facility with filtered air flow and autoclaved cage, food, and water. Mice of 8–12 wk of age were used for the study.
Organism and infection
The mouse pneumonitis biovar of C. trachomatis (MoPn) was grown in HeLa 229 cells and purified by discontinuous density gradient centrifugation. Infectivity of the purified chlamydial elementary bodies (EBs) was titrated by infection of HeLa cell monolayers for 48 h followed by methanol fixation of cells and enumeration of inclusions that were stained by a genus-specific mAb conjugated with horseradish peroxidase. The procedure of MoPn purification and infectivity determination was previously described (33). Mice were inoculated intranasally with various doses of MoPn in a volume of 40 µl. The mice were monitored daily for body weight changes and, as defined in particular experiments, were sacrificed on selected days after infection. To determine the in vivo growth of the organism, the lungs from each mouse were aseptically isolated and homogenized in 4 ml of sucrose phosphate glutamic acid (SPG) buffer. Tissue homogenates were spun down at 500 x g for 10 min at 4°C, and the supernatants were divided into aliquots (1 ml/vial) and kept at -70°C until tested. All samples from the same experiment were tested in the same titration assay, and the leftover thawed samples were not used again for testing of chlamydial infectivity. Repeated tests always used a fresh aliquot of the lung sample.
Serum Ab analysis
Serum IgM, IgG1, IgG2a, and IgA Abs to MoPn EBs were determined by ELISA as previously described (33). Results are expressed as ELISA titers at 60 min using the end point (cutoff at OD405, 0.5) of the titration curves. The results represent the mean ± SEM of the titers of all the sera in the same mouse group.
Determination of DTH responses
MoPn-specific DTH was measured as previously described (33). Mice were injected in the hind footpad with 25 µl of heat-inactivated MoPn EBs (5 x 104 inclusion-forming units (IFU)) in one side and the same volume of SPG buffer in the other side. The difference in thickness between the two footpads at 24, 48, and 72 h was used as a measure of the DTH response. No measurable difference was found between the two footpads injected with heat-inactivated EBs or SPG buffer in uninfected control mice. In experiments examining the effect of local delivery of rIL-10 on DTH responses, heat-inactivated MoPn EBs were injected into footpads in one side with rIL-10 (5 ng/ml) and in the other side without rIL-10. The thicknesses of the footpads were measured before and after MoPn injection. The difference in thickness of each footpad before (0 h) and after (24, 48, and 72 h) heat-inactivated EB (in the presence or the absence of rIL-10) injection was used as a measure of DTH responses.
Histopathological analysis
The lung and footpad injection sites (for DTH analysis) of MoPn-infected mice were examined histopathologically. Lungs were collected on various days following MoPn infection. One lung was used to prepared lung homogenate, and the other was used for histopathological analysis. Footpad injection sites were collected by amputation of the foot at 72 h following heat-inactivated MoPn EB or SPG only (control) injection. All tissues were fixed in 10% neutral buffered formalin, and the footpads were decalcified in 10% formic acid for 5–8 h. Tissues were embedded in paraffin. Five-micron sections were cut, stained with hematoxylin and eosin, and examined by light microscopy. The examination was blinded as to which samples were derived from IL-10 KO and wild-type mice.
Spleen cell culture and cytokine detection
Spleen cells were cultured as previously described (33). Mice
were sacrificed at various days following infection, and spleen cells
were cultured at 7.5 x 106 cells/ml with
heat-inactivated MoPn EBs (1 x 105 IFU/ml) in the
presence or the absence of anti-CD4 (YTS-191) mAb (provided by Dr.
Waldmann, University of Oxford, Oxford, U.K.) at 5 µg/ml or with
rIL-10 (2.5 ng/ml). Culture supernatants were harvested at 72 and
96 h for cytokine determination. IL-12 (p70) was measured using
InterTest-12x, an ELISA kit purchased from Genzyme (Cambridge, MA). The
kit can detect IL-12 at 
10 pg/ml. The determination of other
cytokines was performed using ELISA as previously described (33).
Purified capture and biotinylated detection Abs were purchased from
PharMingen (San Diego, CA). IFN- levels in 72-h culture supernatants
were tested by a two-mAb sandwich ELISA (XMG1.2 for capture and R4–6A2
for detection). IL-5 levels in 96-h culture supernatants were tested
using mAb TRFK as capture Ab and mAb TRFK4 as detector Ab. The TNF-
(72-h supernatants) assay used mAb MP6-XT22 as the capture Ab and
biotinylated rabbit anti-mouse TNF- as the detector Ab.
Recombinant cytokine proteins (PharMingen) were used as standards in
all the assays. Cytokines in the lung homogenates were also tested
using these ELISA.
Statistics
DTH responses and cytokine production were analyzed by Student’s t test. The IFU of MoPn in the infected lungs and serum Ab titers were transformed to base 10 logarithms and analyzed by Student’s t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To examine their susceptibility to chlamydial infection, IL-10 KO
and wild-type mice were intranasally infected with a sublethal dose
(2 x 103 IFU) of MoPn and sacrificed at various times
for analysis of in vivo growth of the organism. As shown in Fig. 1
, although it was similar between these
two groups shortly postinfection (day 1), chlamydial growth in the lung
was about 20-fold (day 7) and 100-fold (day 12) lower in IL-10 KO mice
than in wild-type controls at later stages. Notably, unlike the
observations of intracellular protozoan infections in which IL-10 KO
mice showed more severe disease and higher mortality than wild-type
mice (16, 17, 18), the fast clearance of MoPn lung infection in IL-10 KO
mice was associated with milder disease than that in wild-type mice and
without mortality. The body weight loss (an indicator of morbidity) in
IL-10 KO mice was less, and weight recovery was faster than those in
wild-type mice (Fig. 2). The general
condition of IL-10 KO mice (fur ruffling, dehydration, and activity)
was also better than that of wild-type controls.
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, A and B).
Infiltrates were still present on day 20 in 60% of the mice examined
(Fig. 3, E and F). The infiltrates were similar
in both character and distribution to those in day 7 group. The
remaining 40% showed a lung architecture that was almost completely
normal, with only a few small perivascular infiltrates still
present.
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C).
Unlike the infiltrates in infected IL-10 KO mice, polymorphs were
especially numerous, and bronchi were often seen filled with an
inflammatory exudate rich in neutrophils (Fig. 3D). On day
20, the consolidation had resolved, and >60% of wild-type mice showed
granuloma formation (Fig. 3G) and infiltration by plasma
cells (Fig. 3H), typical of the immunopathological reactions
observed in human chlamydial diseases. Impressively, none of the IL-10
KO mice showed similar immunopathology. In aggregate, the data indicate
that clearance of chlamydial infection in IL-10 KO mice was
significantly accelerated compared with that in wild-type mice,
suggesting that IL-10 may play a role in chlamydia-induced granuloma
formation. IL-10 KO mice acquire rapid and strong DTH responses following MoPn infection
To examine whether the accelerated clearance of chlamydia and the
lack of granuloma formation in IL-10 KO mice were correlated with
alterations in immune responses, we tested humoral and cell-mediated
(DTH) responses in these mice following MoPn infection. MoPn-specific
serum IgM, IgG1, IgG2a, and IgA Ab responses in IL-10 KO mice were not
significantly different from those in wild-type mice, although a trend
for slightly lower Ab responses was observed in IL-10 KO mice (data not
shown). In contrast, DTH responses demonstrated by footpad swelling
following heat-inactivated EB challenge in IL-10 KO mice appeared
earlier and were significantly stronger than those in wild-type mice
(Fig. 4, A and B).
Strong DTH responses in IL-10 KO mice were readily measured on day 7
postinfection, when wild-type mice showed marginal reaction (Fig. 4A). On day 15 postinfection (Fig. 4B), DTH
responses were apparent in both IL-10 KO and wild-type mice, but they
were significantly stronger in IL-10 KO than in wild-type mice.
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CD4 T cells from IL-10 KO mice show increased Th1, but decreased Th2, cytokine production
To directly examine the organism-specific CD4 T cell
cytokine-producing patterns underlining the enhancement of
cell-mediated immune responses, we examined the Th1 (IFN-) and Th2
(IL-4 and IL-5) cytokine production by splenic CD4 T cells collected
from IL-10 KO and wild-type mice. As shown in Fig. 5, IFN- production by spleen cells of
IL-10 KO mice was significantly higher than that of wild-type mice.
Notably, the differences in IFN- levels between wild-type and IL-10
KO mice were more dramatic in the later stages (10- to 20-fold
difference on days 18–20) than in the early stage (5-fold difference
on day 7) of infection. CD4 T cells appeared to be the major source of
IFN-, because addition of anti-CD4 mAb in cell culture blocked
most of the IFN- production (>80%; data not shown). The results
suggest that IL-10 plays an inhibitory role in both the initiation and
expansion stages of Th1-like responses to chlamydial infection, and its
role is more significant for inhibiting Th1-like T cell expansion. On
the other hand, in the early stage of infection (day 7), IL-5
production in IL-10 KO mice was comparable to that in wild-type mice,
while in the late stage of infection (day 20) it was significantly
lower in IL-10 KO mice than that in wild-type controls (Fig. 6). The data suggest that IL-10 is not
essential for Th2-like T cell activation; rather, it may play a role in
Th2-like CD4 T cell expansion in vivo, possibly via inhibition of
Th1-like responses (IFN- production).
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) production
in IL-10 KO mice
The elevated IFN- production and DTH responses in IL-10 KO mice
could imply that these proinflammatory cytokines (TNF- and IL-12)
may also be altered due to the absence of endogenous IL-10. We
therefore examined IL-12 and TNF- production by spleen cells
collected from MoPn-infected IL-10 KO and wild-type mice. As shown in
Fig. 7A, TNF- production by
spleen cells was fourfold higher in IL-10 KO than in wild-type mice at
the early stage (day 7) of infection. At the later stages of infection
(days 18–20), TNF- production was readily detectable in IL-10 KO
mice, although the absolute levels decreased (100–250 pg/ml), while
its production in wild-type mice decreased to undetectable levels (<40
pg/ml). Similarly, high levels of IL-12 production by spleen cells
collected from IL-10 KO mice were also observed, especially at the
early stage of infection (day 7; Fig. 7B). Notably, no
detectable IL-12 production by spleen cells was found in MoPn-infected
wild-type mice upon MoPn in vitro stimulation. The data suggest that
IL-10 can inhibit IL-12 and TNF- production, thereby suppressing
Th1-like responses following chlamydial infection.
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, can result in systemic toxicity, we examined serum TNF- and
IL-12 production. The results showed that virtually no measurable IL-12
(<10 pg/ml) or TNF- (<40 pg/ml) production was present in the sera
of either MoPn-infected IL-10 KO or wild-type mice at any of the time
points tested (days 1, 3, 7, 12, 18, and 20 postinfection). The data
suggest that C. trachomatis infection, unlike intracellular
protozoan infection, does not induce significant systemic cytokine
production.
Elevation of local (lung) IFN- and TNF- production in IL-10
KO mice
In line with the elevated IFN- production by their
splenic CD4 T cells, IFN- levels in the lung homogenates of the
IL-10 KO mice were also higher than those in wild-type mice (Fig. 8). The difference was more obvious in
the later stages of infection (day 20). Marginal levels of IL-5 were
detected at a marginal level in the lung homogenates, and no
significant difference was observed between IL-10 KO and wild-type mice
(data not shown). Local (lung) TNF- levels in IL-10 KO mice were
significantly higher than those in wild-type mice (Fig. 8). In general,
the differences between IL-10 KO and wild-type mice in cytokine levels
in the lung homogenates were not as dramatic as those determined by
organism-specific stimulation of spleen cells. Nevertheless, the data
demonstrate that both intrapulmonary IFN- production and Ag-specific
production of IFN- by splenic lymphocytes were significantly higher
in IL-10 KO than in wild-type mice, suggesting an enhanced Th1-like
response in IL-10 KO mice following chlamydial infection.
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and proinflammatory cytokine
production and DTH responses
To further confirm the inhibitory role of IL-10 in Th1-like
responses during chlamydial infection, we tested the effect of rIL-10
on IFN- and proinflammatory cytokine (TNF- and IL-12) production
by primed spleen cells and on MoPn-specific DTH responses. Addition of
rIL-10 significantly decreased IFN- production by spleen cells
collected from MoPn-infected IL-10 KO mice (Fig. 9A). Exogenous IL-10 also
decreased TNF- (Fig. 9B) and IL-12 production (Fig. 9C). Moreover, injection of rIL-10 into the mouse footpads
suppressed the DTH responses in the MoPn-infected IL-10 KO mice, as
demonstrated by the significantly milder footpad swelling in the
side injected with MoPn plus rIL-10 (5 ng/ml) compared with that in the
side injected with MoPn alone (Fig. 10). Overall, the data demonstrate that
IL-10 inhibits IFN- and proinflammatory cytokine production,
suppressing both in vivo and in vitro cell-mediated immune responses,
delays chlamydial clearance, and is associated with local tissue
immunopathology.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production (33), suggesting that IL-10
plays a crucial role in regulating immune responses in C57BL/6 mice. In
our present study using IL-10 KO mice, we demonstrated that IL-10 is
inhibitory for Th1-like immune responses induced by chlamydial
infection at both the initiation and expansion stages of
organism-specific CD4 T cells, possibly via inhibition of IL-12 and
TNF- production. The inhibitory effect of systemically delivered
rIL-10 on cell-mediated responses has been shown in several model
systems using soluble Ags (38, 39). By local delivery of rIL-10, we now
directly demonstrate that IL-10 can inhibit cell-mediated immune
responses (DTH) following an intracellular bacteria, chlamydial
infection. The combination of results obtained using in vivo and in
vitro approaches clearly demonstrates the role of IL-10 in inhibiting
cell-mediated immunity to chlamydial infection, and the absence of an
inhibitory effect appears beneficial for host resistance to chlamydial
infection. On the other hand, it should be noted that besides its
manipulating effect on cytokine responses noted in the study, IL-10 may
enhance chlamydial infection directly. Obviously, the question cannot
be directly addressed using this gene knockout model because the lack
of IL-10 and the increase in the Th1-like response were both present in
these mice in the process of chlamydial infection. The fact that IL-10
KO and wild-type mice had similar levels of chlamydial growth on day 1
postinfection (Fig. 1) suggest that mice can be infected equally by
chlamydia with or without the presence of IL-10 in vivo. Moreover,
although its level was remarkably less than that in IL-10 KO mice,
IFN- production in wild-type mice was also readily measurable (Fig. 5A). This may be why wild-type mice also resolved chlamydial
infection eventually. IL-12 (p70) production was not measurable at the
time of determination in wild-type mice. This may suggest that IL-12
was either more transiently expressed or was too low to be detected in
wild-type mice. The data may also suggest that IL-12, although capable
of enhancing Th1-like responses and thereby accelerating organism
clearance, is not necessary for resolution of chlamydial infection.
A novel and unexpected finding in the present study is the difference
in the immunopathologic responses (granuloma formation, plasma cell
infiltration, and tissue fibrosis) between wild-type and IL-10 KO mice.
In the later stages of infection (day 20), when most organisms have
been cleared in both wild-type and IL-10 KO mice, wild-type, but not
IL-10 KO, mice showed plasma cell infiltration and granuloma formation.
Although classically described as a DTH response associated with Th1
cytokine, granuloma formation is currently suggested to be due to
Th2-related cytokine responses (40, 41, 42) and can be suppressed by
Th1-related cytokines (43, 44). Moreover, vaccination with schistosome
eggs and IL-12 inhibits both granuloma formation and tissue fibrosis
induced by natural Schistosoma mansoni infection (44, 45).
Since the IL-10 KO mice produce significantly higher levels of IL-12
and IFN- than wild-type mice and are deficient in granuloma
formation, we hypothesize that the increased levels of IL-12 and
IFN- of these cytokines may be involved in the prevention of
immunopathologic (granulomatous) reaction.
The alteration in IL-5 production in IL-10 KO mice suggests that
IL-10 may also promote Th2 cytokine production. Variable results have
been reported regarding the role of IL-10 in influencing Th2-like cell
differentiation (46, 47, 48, 49). One study showed that IL-10, similar to IL-4,
promoted Th2-like cell differentiation in TCR transgenic mice (46),
while another study showed that IL-10 had little effect on skewing Th1-
or Th2-like cell differentiation (47). We found that IL-5 production in
IL-10 KO and wild-type mice was comparable at the early stage (day 7)
of infection, but was different in the later stages, with lower IL-5
levels in IL-10 KO mice. We speculate that the decrease in IL-5
production in the later, but not the early, stages of infection in
IL-10 KO mice may reflect an indirect effect mediated by persistent
elevation of IFN- and/or other Th1-promoting cytokines that are
inhibitory for the development of Th2-like cells due to the absence of
immunoregulating amounts of IL-10.
The data in the present study are in striking contrast to those
obtained from intracellular protozoan infection models in terms of
acute toxicity. Although the reason for the difference remains unclear,
we speculate that it may reflect the differences in the natural
pathogenesis among these infections and in the immunoregulating
mechanism(s) involved in the pathogenesis. For example, it has been
shown that Toxoplasma gondii possesses a superantigen that
can expand a large percentage of T cells (50), and IL-10 has been shown
to play a critical role in inhibiting superantigen-induced T cell
activation (51). There is no evidence that chlamydia carries a
superantigen. Moreover, intranasal inoculation of MoPn, unlike
intracellular protozoan infections, causes mainly local (respiratory)
chlamydial growth and inflammatory reaction. Thus, virtually no
detectable (<10–40 pg/ml) IL-12 and TNF- were measured in the sera
of wild-type and IL-10 KO mice following chlamydial infection. Indeed,
although IL-12 and TNF- production in spleen cells from IL-10 KO
mice was increased in the early stage of chlamydial infection (day 7;
Fig. 8), IL-12 and TNF- production in IL-10 KO mice was transient
(decrease to marginal levels on day 20) and was not detectable in the
serum above the testing sensitivity level (10 pg/ml). This difference
in systemic cytokine production may be critical in explaining the
difference in the outcome (death or survival) of IL-10 KO mice
following intracellular protozoan and chlamydial infection. This point
was particularly supported by the finding that the earlier mortality of
IL-10 KO mice following Trypanosoma cruzi (18) was
associated with overwhelming systemic (serum) release of IL-12 and
TNF- and that it was reversed by neutralizing endogenous IL-12 or
TNF- with anti-IL-12 or anti-TNF- Abs.
Finally, although no significant acute toxicity has been found in the
MoPn-infected IL-10 KO mice, this does not mean that the inhibitory
effect of IL-10 on Th1-like responses is not relevant to host
homeostasis during chlamydial infection. In fact, one interesting
finding in this study was that the difference in IFN- production
between wild-type and IL-10 KO mice (persistently higher IFN- levels
in IL-10 KO mice) was more dramatic at the later stages of chlamydial
infection when IFN- levels had significantly decreased in wild-type
mice (Fig. 6). The long term effect of the persistent elevation of
IFN- was not examined in the present study. Since IL-10 KO mice
showed elevated IFN- production and an absence of granuloma
formation, which is relevant to the sequelae (blindness and
infertility) induced by chlamydial infection, the results suggests that
modulation of IL-10 production could be an approach to prevent sequelae
of chlamydial infection. Obviously, further studies, especially
those dealing with the long term effects of the absence of endogenous
IL-10, are required for rational development of chlamydial
immunoprophylactic approaches.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Xi Yang, Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, Room 523, 730 William Ave., Winnipeg, Manitoba, Canada R3E OW3. E-mail address:
3 Abbreviations used in this paper: KO, knockout; DTH, delayed-type hypersensitivity; MoPn, Chlamydia trachomatis mouse pneumonitis; EB, elementary body; SPG, sucrose phosphate glutamic acid buffer; IFU, inclusion-forming units.
Received for publication May 8, 1998. Accepted for publication September 29, 1998.
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L. Bilenki, S. Wang, J. Yang, Y. Fan, L. Jiao, A. G. Joyee, X. Han, and X. Yang Adoptive Transfer of CD8{alpha}+ Dendritic Cells (DC) Isolated from Mice Infected with Chlamydia muridarum Are More Potent in Inducing Protective Immunity Than CD8{alpha}- DC J. Immunol., November 15, 2006; 177(10): 7067 - 7075. [Abstract] [Full Text] [PDF]
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L. Bilenki, S. Wang, J. Yang, Y. Fan, A. G. Joyee, and X. Yang NK T Cell Activation Promotes Chlamydia trachomatis Infection In Vivo J. Immunol., September 1, 2005; 175(5): 3197 - 3206. [Abstract] [Full Text] [PDF]
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M. J. Burton, R. L. Bailey, D. Jeffries, D. C. W. Mabey, and M. J. Holland Cytokine and Fibrogenic Gene Expression in the Conjunctivas of Subjects from a Gambian Community Where Trachoma Is Endemic Infect. Immun., December 1, 2004; 72(12): 7352 - 7356. [Abstract] [Full Text] [PDF]
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R. A. Hawkins, R. G. Rank, and K. A. Kelly A Chlamydia trachomatis-Specific Th2 Clone Does Not Provide Protection against a Genital Infection and Displays Reduced Trafficking to the Infected Genital Mucosa Infect. Immun., September 1, 2002; 70(9): 5132 - 5139. [Abstract] [Full Text] [PDF]
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R. Lang, R. L. Rutschman, D. R. Greaves, and P. J. Murray Autocrine Deactivation of Macrophages in Transgenic Mice Constitutively Overexpressing IL-10 Under Control of the Human CD68 Promoter J. Immunol., April 1, 2002; 168(7): 3402 - 3411. [Abstract] [Full Text] [PDF]
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H. K. Maxion and K. A. Kelly Chemokine Expression Patterns Differ within Anatomically Distinct Regions of the Genital Tract during Chlamydia trachomatis Infection Infect. Immun., March 1, 2002; 70(3): 1538 - 1546. [Abstract] [Full Text] [PDF]
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V. Dheenadhayalan, S. Shanmugalakshmi, S. Vani, P. Muthuveeralakshmi, G. Arivarignan, A. D. Nageswari, and R M. Pitchappan Association of Interleukin-10 Cytokine Expression Status with HLA Non-DRB1*02 and Mycobacterium bovis BCG Scar-Negative Status in South Indian Pulmonary Tuberculosis Patients Infect. Immun., September 1, 2001; 69(9): 5635 - 5642. [Abstract] [Full Text] [PDF]
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I. V. Lyadova, E. B. Eruslanov, S. V. Khaidukov, V. V. Yeremeev, K. B. Majorov, A. V. Pichugin, B. V. Nikonenko, T. K. Kondratieva, and A. S. Apt Comparative Analysis of T Lymphocytes Recovered from the Lungs of Mice Genetically Susceptible, Resistant, and Hyperresistant to Mycobacterium tuberculosis-Triggered Disease J. Immunol., November 15, 2000; 165(10): 5921 - 5931. [Abstract] [Full Text] [PDF]
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J. U. Igietseme, G. A. Ananaba, J. Bolier, S. Bowers, T. Moore, T. Belay, F. O. Eko, D. Lyn, and C. M. Black Suppression of Endogenous IL-10 Gene Expression in Dendritic Cells Enhances Antigen Presentation for Specific Th1 Induction: Potential for Cellular Vaccine Development J. Immunol., April 15, 2000; 164(8): 4212 - 4219. [Abstract] [Full Text] [PDF]
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K. A. Kelly, J. C. Walker, S. H. Jameel, H. L. Gray, and R. G. Rank Differential Regulation of CD4 Lymphocyte Recruitment between the Upper and Lower Regions of the Genital Tract during Chlamydia trachomatis Infection Infect. Immun., March 1, 2000; 68(3): 1519 - 1528. [Abstract] [Full Text] [PDF]
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A. K. H. Mertz, P. Wu, T. Sturniolo, D. Stoll, M. Rudwaleit, R. Lauster, J. Braun, and J. Sieper Multispecific CD4+ T Cell Response to a Single 12-mer Epitope of the Immunodominant Heat-Shock Protein 60 of Yersinia enterocolitica in Yersinia-Triggered Reactive Arthritis: Overlap with the B27-Restricted CD8 Epitope, Functional Properties, and Epitope Presentation by Multiple DR Alleles J. Immunol., February 1, 2000; 164(3): 1529 - 1537. [Abstract] [Full Text] [PDF]
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Y. Fan, S. Wang, and X. Yang Chlamydia trachomatis (Mouse Pneumonitis Strain) Induces Cardiovascular Pathology following Respiratory Tract Infection Infect. Immun., November 1, 1999; 67(11): 6145 - 6151. [Abstract] [Full Text] [PDF]
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W. Ma, W. Lim, K. Gee, S. Aucoin, D. Nandan, M. Kozlowski, F. Diaz-Mitoma, and A. Kumar The p38 Mitogen-activated Kinase Pathway Regulates the Human Interleukin-10 Promoter via the Activation of Sp1 Transcription Factor in Lipopolysaccharide-stimulated Human Macrophages J. Biol. Chem., April 20, 2001; 276(17): 13664 - 13674. [Abstract] [Full Text] [PDF]
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) and IL-10 KO (
) mice
were intranasally infected with MoPn (2000 IFU) and sacrificed on
various days postinfection. The lung tissues were analyzed for in vivo
chlamydial growth as described in Materials and Methods.
Each point represents the mean ± SD of IFU (log10) for five or
six mice. *, p < 0.05
) mice.
Mice were intranasally infected with MoPn (2000 IFU) and were monitored
daily for body weight change. Each point represents the mean ± SD
of five mice.
)
compared with wild-type mice (
