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Department of Veterinary Biosciences, Ohio State University, Columbus, OH 43210
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-/- or
C57BL/6IL-10-/- mice. Four or eight weeks after transfer,
DTH to H. pylori Ags was determined by footpad
injection; gastritis and bacterial colonization were quantified; and
IFN- secretion by splenocytes in response to H.
pylori Ag was determined. Gastritis and DTH were present in
recipients of unfractionated splenocytes, CD4+ splenocytes,
and CD4+CD45RBhigh splenocytes, but absent in
the other groups. IFN- secretion in response to H.
pylori Ags was correlated with gastritis, although splenocytes
from all groups of mice secreted some IFN-. Gastritis was most
severe in recipients of splenocytes from IL-10-deficient mice, and
least severe in those given IFN--deficient splenocytes. Bacterial
colonization in all groups was inversely correlated with gastritis.
These data indicate that 1) CD4+ T cells are both necessary
and sufficient for gastritis and DTH due to H. pylori in
mice; 2) high expression of CD45RB is a marker for gastritis-inducing
CD4+ cells; and 3) IFN- contributes to gastritis and
IL-10 suppresses it, but IFN- secretion alone is not sufficient to
induce gastritis. The results support the assertion that H.
pylori is mediated by a Th1-biased cellular immune
response. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, IL-8), and gastric mucosa
is infiltrated with proinflammatory Th1-biased lymphocytes as well as
neutrophils and other inflammatory cell types (2, 3, 4, 5).
Because of the difficulty of performing invasive studies in humans,
much of our understanding of the immune basis of H.
pylori-related disease comes from studies in mice. Like humans
infected with H. pylori, mice infected with the closely
related Helicobacter felis respond to infection with
infiltration of Th1-biased lymphocytes into the gastric mucosa and
spleen. IFN- becomes elevated in tissue, and splenic Th cells
respond to H. pylori Ag by secreting high levels of IFN-
and undetectable levels of IL-4 (6). Furthermore, when
infected with H. felis, IFN--deficient genetic knockout
mice fail to develop any gastritis (7, 8), while IL-10
knockout mice develop gastritis that is much more severe than in
wild-type mice (9). Finally, splenic lymphocytes from
nonresponder mouse strains that do not develop gastritis in response to
gastric helicobacters express IL-10, but not IFN-, in response to
H. pylori Ag (10). These data suggest that
Th1-biased cellular immune responses largely determine the outcome of
gastric Helicobacter infection in mice.
Ig response does not appear to determine outcome of infection. Mice
that are genetically unable to produce Ab respond to both infection and
vaccination identically to normal mice (11, 12), whereas
IFN--deficient mice are not able to suppress bacterial infection to
the same extent as wild-type mice (7). Finally, adoptive
transfer of CD4+ lymphocytes into H.
felis-infected mice exacerbates gastritis in the recipients
(6). Thus, cellular rather than humoral immune responses
control both gastritis and suppression of colonization.
Data from our laboratory demonstrate that H. pylori-infected
mice respond similarly to humans and to H. felis-infected
mice. Adoptive transfer of splenocytes from C57BL/6 mice to congenic
SCID mice results in preferential engraftment of T cells, severe
gastritis with concurrent development of a delayed-type
hypersensitivity
(DTH)3 response to
H. pylori Ags, and development of a blastogenic response of
CD4+ splenocytes to H. pylori Ag
(13). In contrast, humoral immune response develops late
and does not correlate with gastritis. Gastritis in infected recipient
mice is widespread and rapidly developing. It resembles gastritis in
H. pylori-infected humans both morphologically, with
infiltration of lymphocytes, macrophages, and neutrophils, atrophy of
gastric parietal cells, and epithelial erosions, and immunologically,
with elevation of IFN- production by stimulated lymphocytes.
The purpose of the current study was to investigate the
immunopathogenesis of severe gastritis in H. pylori-infected
recipient SCID mice. H. pylori-infected recipient SCID mice
received unfractionated splenocytes, CD4+
splenocytes, or CD4-depleted splenocytes to determine whether Th cells,
non-T cells, or both are capable of inducing gastritis. In addition,
the role of CD4+ cells expressing the surface
marker CD45RB was evaluated. Finally, the role of T cell-derived IL-10
and IFN- in suppression or promotion of gastritis mice was
determined.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6, C57BL/6-Prkdcscid (SCID),
C57BL/6IL10-/- (IL-10-deficient), and
C57BL/6IFN--/-
(IFN--deficient) mice, 4–6 wk old, were purchased from
Helicobacter-free colonies at The Jackson Laboratory (Bar
Harbor, ME). Immune incompetence of SCID mice was verified by the
absence of murine IgG, as detected by ELISA (13). Mice
were kept in sterile microisolator cages in a barrier facility, and fed
sterile water and Teklad lab chow ad libitum (Teklad, Madison, WI). A
total of 240 mice were used in this study. All procedures involving
animals were approved by the Ohio State University institutional
laboratory animal care and use committee.
Bacteria
H. pylori strain SS1, a mouse-adapted human isolate, was grown on 5% sheep blood agar plates or in Brucella broth with 10% FCS. For preparation of sonicates and for mouse inoculation, bacteria were grown in broth overnight at 37°C in a microaerobic environment with gentle agitation. Bacterial sonicates for footpad injection and T cell stimulation were prepared as previously described (13).
Bacterial infection and adoptive transfer
Details of the adoptive transfer mouse model used in this study
have been previously published (13). Briefly, splenocytes
from normal, uninfected C57BL/6 mice were transferred to H.
pylori-infected SCID mice by i.p. injection. Adoptive transfer was
performed 4 wk after oral inoculation of SCID mice with
108 CFU of live, broth-cultured H.
pylori. To ensure approximately equivalent numbers of engrafted T
cells, each mouse received 1 x 106
unfractionated splenocytes (
20% CD4+ T cells,
as determined by flow cytometry; Ref. 13), 2 x
105 CD4+ splenocytes, or
8 x 105 CD4-depleted splenocytes. This
protocol results in engraftment of T or T and B lymphocytes and
development of cellular or cellular and serologic immune responses to
H. pylori in the recipient mice (13). In
contrast to infected normal C57BL/6 mice, which develop minimal to mild
cellular immune responses and mild gastritis, infected SCID recipients
of unfractionated splenocytes develop strong cellular immune responses
that result in DTH responses to H. pylori Ags and severe
gastritis within 4 wk of adoptive transfer (13).
Cell fractionation
Spleens were removed immediately after death and placed in sterile HBSS, pH 7, at 4°C. Splenocytes were isolated by disaggregation and hypotonic lysis, washed in PBS, and stained with FITC- or PE-labeled Ab against CD4, and in some cases CD45RB, as previously described (13). Cells were separated with a Coulter EPICS 753 dye laser cell sorter (Coulter Pharmaceutical, Palo Alto, CA). The CD4+ fraction contained 95–98% CD4+ cells, and the CD4-depleted fraction contained <1% CD4+ cells, as determined by restaining and recounting. For fractionation according to CD45RB expression, double-labeled cells were sorted first to collect CD4+ cells, and then the CD4+ fraction was separated into two fractions according to intensity of CD45RB fluorescence, as described by Morrissey (14). Two populations of cells were recognizable based on fluorescence intensity. The brightest staining 40% was designated CD45RBhigh and the dullest staining 15% was designated CD45RBlow.
Experimental design
Infected or uninfected SCID mice received either unfractionated
(total) splenocytes, CD4+ splenocytes, CD4
splenocytes fractionated according to CD45RB expression, or
CD4-depleted splenocytes. All splenocytes were from uninfected C57BL/6,
C57BL/6IL-10-/-, or
C57BL/6IFN--/- mice.
Uninfected mice (both recipient and donor groups) developed no lesions,
no serum immune responses, and no footpad swelling in response to
H. pylori Ag. Results from these groups are not shown in all
cases. Recipients of unfractionated splenocytes,
CD4+ splenocytes, CD4-depleted splenocytes, or
splenocytes from
C57BL/6IFN--/- mice
were killed 4 or 8 wk after transfer. Recipients of
CD45RBhigh or CD45RBlow
splenocytes or splenocytes from IL-10-deficient mice were killed 4 wk
after transfer. In these groups, lesions were maximal by 4 wk after
transfer, and 8-wk groups were not included. IL-10-deficient mice and
C57BL/6 controls were killed 8 wk after inoculation. Each experimental
and control group had between 5 and 20 mice. The number of mice in
individual experiments is indicated in
Figs. 1–5
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ELISA
H. pylori-specific serum IgG and IgM were determined as previously described (13). Briefly, plates were coated with 100 µg/ml H. pylori SS1 sonicate for 48 h at 4°C, washed, blocked with blocking buffer (1 g/L gelatin in 0.1 M PBS + 0.02% sodium azide), washed again, and incubated for 90 min at 37°C with terminal mouse sera diluted 1/50. Plates were then washed again, incubated with alkaline phosphatase-conjugated goat anti-mouse IgM or IgG (Bio-Rad, Richmond, CA), and washed, and alkaline phosphatase was detected with an alkaline phosphatase substrate kit (Bio-Rad), according to the manufacturer’s instructions.
Lymphocyte culture and IFN- ELISA
Splenocytes were isolated by disaggregation and hypotonic lysis
(13). To ensure sufficient numbers of cells for analysis,
spleens from five recipient SCID mice per group were combined. Thus,
each assay represented five individual mice. Nonrecipient SCID spleens
had no identifiable splenic lymphocytes, and thus could not be
evaluated. Between one and five assays (representing 5–25 different
mice) were evaluated for each experimental group. Sterile 96-well
culture dishes were seeded with 1 x 106
washed splenocytes/well in RPMI 1640, and Ag (1 µg/ml) or mitogen
(Con A, 25 µg/ml) was added. Ag was either sonicated H.
pylori prepared as described above or whole washed H.
pylori cells resuspended to 1 x 108
cells/ml in PBS with 1% Formalin added. Control wells were treated
with medium alone. Splenocytes were incubated for 5 days at 37°C in
5% CO2, and the medium were removed and stored
at -70°C until used. For IFN- determination, a commercially
available kit was used according to the manufacturer’s instructions
(PharMingen, San Diego, CA).
Histologic evaluation
For quantification of gastritis, hematoxylin and eosin-stained sections were scored for lymphocytic and neutrophilic inflammation and gastric epithelial metaplasia, as previously described (13). Briefly, sections were examined under x200 magnification, and the percentage of fields containing inflammatory infiltrate sufficient to displace glands (gastritis), neutrophilic infiltration (polymorphonuclear), and/or loss of normal fundic morphology with replacement by undifferentiated mucus-type glands (metaplasia) was determined. In this way, the extent of inflammatory lesions, which correlates with severity, was quantified. This method is less subjective than semiquantitative scoring methods because percentage of affected mucosa can be quantified based on presence or absence of lesions rather than an estimate of severity. Results reflect differences in mouse groups, as previously demonstrated (13, 15).
Statistics
Group means were compared by nonparametric methods (Mann-Whitney U test) or by ANOVA with Fisher’s protected least significant difference to compare individual groups. Values in the text are expressed as mean ± SD. Statistical significance was set at p < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Four weeks after transfer, infected SCID recipients of either
unfractionated splenocytes or CD4+ splenocytes
from C57BL/6 donors developed marked gastric inflammation compared with
nonrecipient mice or uninfected controls (Fig. 1
). All three indicators of gastric
damage, gastritis, neutrophil infiltration, and metaplasia, were
increased. In contrast, recipients of CD4-depleted splenocytes did not
develop gastric lesions (p = 0.961, compared
with nonrecipient controls). Fractionation of
CD4+ cells according to the CD45RB marker also
revealed differences between the subsets (Fig. 1). Recipients of
CD+CD45RBhigh splenocytes
developed gastritis that did not differ significantly from recipients
of CD4+ or unfractionated splenocytes, whereas
recipients of CD4+CD45RBlow
splenocytes did not develop gastric lesions. Gastric lesions in
mice killed 8 wk after transfer were similar to lesions in mice killed
after 4 wk (data not shown).
Indicators of immune response also differed between the groups. Humoral
immune response, as indicated by H. pylori-specific IgG,
developed only in recipients of unfractionated splenocytes, confirming
that only this group received both T and B lymphocytes (Fig. 2). The only other mice to develop
H. pylori-specific Abs were recipients of CD4-depleted
splenocytes killed 8 wk after transfer. These mice developed low levels
of IgM, but maturation of the immune response did not occur, most
likely because of the absence of Th cells. In contrast to humoral
immune response, cellular immune response as measured by DTH response
correlated with severity of gastric lesions. Four weeks after transfer,
mean footpad swelling in recipients of unfractionated splenocytes
(3.2 ± 3.4 mm) and CD4+ splenocytes
(5.3 ± 4.1 mm) was significantly greater than in recipients of
CD4-depleted splenocytes (0.7 ± 0.5 mm) and nonrecipients
(0.2 ± 0.2 mm) (p < 0.0001).
Bacterial colonization was inversely correlated to extent of gastric
lesions. Gastritis in recipients of unfractionated splenocytes was
associated with suppression of colonization both 4 and 8 wk after
transfer (p < 0.0001 compared with
nonrecipients, Fig. 3; 8-wk interval not
shown). Similarly, 4 wk after transfer, colonization was suppressed in
recipients of CD4+ or
CD4+CD45RBhigh splenocytes,
but not in recipients of
CD4+CD45RBlow splenocytes
(Fig. 3).
Response of sensitized splenocytes to H. pylori Ags in vitro
IFN- secretion in vitro in response to H. pylori Ags
(either Formalin-fixed bacteria or sonicate) partly correlated with
extent of gastritis and DTH response. The greatest H.
pylori-induced IFN- secretion was by splenocytes recovered from
infected SCID recipients of CD4+ splenocytes, the
group that also developed the strongest DTH response, and the most
extensive gastric lesions (Fig. 4).
Splenocytes from both infected and uninfected C57BL/6 and SCID
recipient mice secreted IFN-, although secretion was significantly
higher in splenocytes from infected mice (Fig. 4). This suggests that
H. pylori Ags induce both specific and nonspecific responses
from host splenocytes. Both specific and nonspecific IFN- responses
to Formalin-fixed (surface) Ag were consistently higher than response
to sonicated (soluble) Ag (Fig. 4), but these differences were not
significant. Surprisingly, splenocytes recovered from infected
recipients of CD4-depleted splenocytes or
CD4+CD45RBlow splenocytes
and from uninfected recipients of CD4+
splenocytes also secreted IFN- in response to H. pylori
Ag, despite the absence of DTH response and gastritis. Failure of
splenocytes from recipients of
CD+CD45RBlow cells to
respond to either Con A or anti-CD3 despite their
CD4+ phenotype has been previously reported
(16). Nonrecipient mice could not be evaluated because
they had insufficient numbers of splenocytes.
Recipients of splenocytes from IL-10- or IFN--deficient mice
In both donor IL-10-deficient mice and SCID recipients of
IL-10-deficient splenocytes, gastritis, neutrophilic infiltration, and
epithelial metaplasia were more extensive than in wild-type controls
and recipients (Fig. 5). Concurrently,
bacterial colonization was more effectively suppressed in
IL-10-deficient mice than in C57BL/6 mice (5 x
104 CFU/g compared with 2.37 x
107 CFU/g, p = 0.016) and in
recipients of IL-10-deficient splenocytes compared with recipients of
normal splenocytes (4 ± 5 x 104
compared with 1.1 ± 1.2 x 106 CFU/g,
p > 0.0001). In contrast, IFN--deficient
splenocytes induced less extensive gastric lesions (Fig. 5) and
suppressed colonization less extensively than wild-type splenocytes.
Four weeks after transfer, only small differences were present, but by
8 wk after transfer, gastritis was significantly less in recipients of
IFN--deficient splenocytes (p = 0.0002, Fig. 5) compared with recipients of normal splenocytes. Colonization was
greater in recipients of IFN--deficient splenocytes (4.8 ±
5.8 x 106 CFU/g) than in recipients of
normal splenocytes (1 ± 2 x 105
CFU/g), but the difference did not reach statistical significance.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The clear role of CD4+/CD45RBhigh T cells in induction of gastritis, demonstrated in this study, is evidence that gastritis due to H. pylori is most likely representative of a common mechanism characteristic of several other inflammatory diseases, including inflammatory bowel disease (IBD) and possibly autoimmune diseases in mice (14, 16, 17, 18, 19, 20). These diseases differ in the inciting Ag (luminal bacteria in the case of H. pylori gastritis and IBD, and self Ags in the case of autoimmune diseases), but appear similar in that they are caused by an imbalance in progressor and regulatory CD4 subsets. Adoptively transferred progressor cells expressing CD4 and high levels of CD45RB surface markers induce inflammation in immunodeficient recipients, while regulatory cells expressing CD4, in some studies CD25 (IL-2R, an activation marker) (16), and low levels of CD45RB do not induce inflammation, and in fact protect recipients from inflammation induced by CD45RBhigh cells (17). It remains to be determined whether activated CD45RBlow cells are protective against H. pylori gastritis as they are in other diseases, but the similarity of these diseases is strongly suggestive of a common mechanism. In contrast to the studies cited above in which transfer of CD4+ or CD4+CD45RBhigh splenocytes alone induced IBD, we did not observe lower bowel disease in our mice (data not shown). The absence of enteric helicobacter species in our mice may explain this difference. It is likely that enteric helicobacter were at least in part responsible for IBD in recipient mice in the published studies (21).
The data reported in this study support assertions that cellular rather than humoral immunity determines the outcome of H. pylori infection. Several studies have shown that failure of Ig production (in µMT-deficient and MHC II-deficient mice) has no effect on either gastritis or bacterial colonization (11, 12, 22), but the absence of immune cells completely eliminates gastritis (13, 22), suggesting that cellular rather than humoral immune response determines outcome of infection. More specifically, several studies done in mice infected with the related bacterium, H. felis, have indicated that cellular immune responses are central. Mohammadi et al. (5, 6) showed that adoptive transfer of CD4+ cells to immunocompetent mice exacerbated gastritis, and Roth et al. (22) showed that transfer of CD4+ cells induced gastritis in H. felis-infected immunodeficient C57BL/6RAG1-/- mice. We have extended these findings to H. pylori-infected mice and confirmed that humoral immunity is not necessary for full expression of gastritis.
Like other studies (2, 3, 5, 7, 8), our data indicate a
role for IFN- in induction of gastritis. The expression of IFN-
by CD4+ splenocytes in response to H.
pylori Ags is consistent with previous studies indicating that
H. pylori induces a Th1-biased immune response and is
associated with increased levels of IFN- in infected humans and mice
(2, 3, 7, 8, 10). In addition, our finding that 8 wk after
transfer, splenocytes from IFN--deficient mice induced less
extensive gastritis than did splenocytes from wild-type mice indicates
at least some role for IFN-. This was true even though normal SCID
mice have NK cells that may secrete IFN-. It indicates that IFN-
secretion by sensitized T cells themselves is necessary, and is
congruent with previous studies demonstrating the absence of gastritis
in IFN--deficient mice (7, 8).
Despite these indications that IFN- has a role in H.
pylori gastritis, we also showed that IFN- secretion alone is
not sufficient to induce gastritis. H. pylori Ags stimulated
IFN- secretion by splenocytes from all mice examined, including
infected and uninfected C57BL/6 and infected and uninfected SCID
recipients of either CD4+ or CD4-depleted
lymphocytes, despite the absence of either DTH or gastritis in some of
these mice. This finding suggests that while IFN- may be necessary
for induction of gastritis, it is not sufficient. Unlike previous
studies (23), we did demonstrate significantly higher
IFN- secretion in infected mice and in mice given
CD4+ and
CD4+CD45RBhigh cells
compared with the other cell populations, suggesting that sensitization
of lymphocytes may enhance secretory response. However, clearly there
is a strong nonspecific component as well.
These results are not unprecedented. A recently published study
investigating the inheritance of H. pylori nonresponsiveness
in mice demonstrated that while IFN- secretion correlated with
gastritis in inbred parental mouse strains, splenocytes from hybrid
F1 generation mice secreted high levels of
IFN- without induction of gastritis. The authors of that study
suggested that high levels of IL-10 also demonstrated in
F1 mice may have masked the proinflammatory
effects of IFN-, presumably by suppressing TNF-
or other
macrophage products. The role of other costimulatory or regulatory
cytokines in H. pylori gastritis must be further
examined.
The Th1 bias of H. pylori gastritis is further supported by our finding that IL-10-deficient mice in this study developed more severe gastritis than did normal control mice, and that recipients of IL-10-deficient splenocytes developed more severe gastritis than did recipients of normal splenocytes. These findings are compatible with previous studies in which H. felis induced more severe gastritis in IL-10-deficient mice than in normal mice (9). A new finding in the current study was that splenocytes from IL-10-deficient mice were more effective at induction of disease and suppression of colonization than were splenocytes from normal mice. However, this difference was small, and it suggests that transferred splenocytes from normal mice contain few IL-10-secreting cells. Thus, even in splenocytes from normal mice, the regulatory effect of IL-10 in SCID recipients is small, and loss of this regulatory control in IL-10-deficient mice only results in a small exacerbation of gastritis.
The primary new findings presented in this study are that
CD4+ lymphocytes are necessary and sufficient for
induction of gastritis in H. pylori-infected SCID mice, that
high expression of CD45RB is a marker for gastritis-inducing
CD4+ cells, that IFN- secretion alone in
response to H. pylori is not sufficient to induce gastritis
by splenocytes, and that splenocytes from IL-10-deficient donors induce
gastritis that is somewhat more severe than splenocytes from normal
donors. These results are compatible with previous findings in both
mice and humans suggesting that H. pylori gastritis is a
Th1-mediated disease induced by contact with bacterial Ags, and
suppressed by IL-10. Finally, these results add to the increasing body
of data that suggest that differences in severity of disease between
different patients may be attributable to differences in local Th
immune responses. Evaluation of this hypotheses will require
examination of human tissues from patients with varying responses to
H. pylori colonization.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Kathryn A. Eaton, Department of Veterinary Biosciences, Ohio State University, 1925 Coffey Road, Columbus, OH 43210. E-mail address: eaton.1{at}osu.edu
3 Abbreviations used in this paper: DTH, delayed-type hypersensitivity; IBD, inflammatory bowel disease.
Received for publication March 27, 2001. Accepted for publication April 12, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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interferon in Helicobacter pylori-induced gastric inflammatory responses in a mouse model. Infect. Immun. 67:279., gene-deficient mice. J. Immunol. 165:1022. interferon. Infect. Immun. 68:4802.
T cell receptor. Eur. J. Immunol. 25:1643.[Medline]
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K. A. Eaton, S. M. Logan, P. E. Baker, R. A. Peterson, M. A. Monteiro, and E. Altman Helicobacter pylori with a Truncated Lipopolysaccharide O Chain Fails To Induce Gastritis in SCID Mice Injected with Splenocytes from Wild-Type C57BL/6J Mice Infect. Immun., July 1, 2004; 72(7): 3925 - 3931. [Abstract] [Full Text] [PDF]
|
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|
|
|
Y. Zavros, J. Y. Kao, and J. L. Merchant Inflammation and Cancer III. Somatostatin and the innate immune system Am J Physiol Gastrointest Liver Physiol, May 1, 2004; 286(5): G698 - G701. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Akhiani, K. Schon, L. E. Franzen, J. Pappo, and N. Lycke Helicobacter pylori-Specific Antibodies Impair the Development of Gastritis, Facilitate Bacterial Colonization, and Counteract Resistance against Infection J. Immunol., April 15, 2004; 172(8): 5024 - 5033. [Abstract] [Full Text] [PDF]
|
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M. Macarthur, G. L. Hold, and E. M. El-Omar Inflammation and Cancer II. Role of chronic inflammation and cytokine gene polymorphisms in the pathogenesis of gastrointestinal malignancy Am J Physiol Gastrointest Liver Physiol, April 1, 2004; 286(4): G515 - G520. [Abstract] [Full Text] [PDF]
|
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H. F. Ismail, J. Zhang, R. G. Lynch, Y. Wang, and D. J. Berg Role for Complement in Development of Helicobacter-Induced Gastritis in Interleukin-10-Deficient Mice Infect. Immun., December 1, 2003; 71(12): 7140 - 7148. [Abstract] [Full Text] [PDF]
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 |
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 Y. Zavros, S. Rathinavelu, J. Y. Kao, A. Todisco, J. Del Valle, J. V. Weinstock, M. J. Low, and J. L. Merchant Treatment of Helicobacter gastritis with IL-4 requires somatostatin PNAS, October 28, 2003; 100(22): 12944 - 12949. [Abstract] [Full Text] [PDF]
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F. Meyer, K. S. Ramanujam, A. P. Gobert, S. P. James, and K. T. Wilson Cutting Edge: Cyclooxygenase-2 Activation Suppresses Th1 Polarization in Response to Helicobacter pylori J. Immunol., October 15, 2003; 171(8): 3913 - 3917. [Abstract] [Full Text] [PDF]
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S Futagami, T Hiratsuka, A Tatsuguchi, K Suzuki, M Kusunoki, Y Shinji, K Shinoki, T Iizumi, T Akamatsu, H Nishigaki, et al. Monocyte chemoattractant protein 1 (MCP-1) released from Helicobacter pylori stimulated gastric epithelial cells induces cyclooxygenase 2 expression and activation in T cells Gut, September 1, 2003; 52(9): 1257 - 1264. [Abstract] [Full Text]
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