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Digestive Health Center of Excellence, University of Virginia, Charlottesville, VA 22908
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(prevention: 0.53 ± 0.21
vs 1.84 ± 0.04 ng/ml, p < 0.05; treatment:
8.4 ± 0.4 vs 12.4 ± 0.7 ng/ml, p <
0.005) and TNF (prevention: 61.5 ± 13 vs 134 ± 19 pg/ml,
p < 0.01; treatment: 333.5 ± 11 vs 496
± 20 pg/ml, p < 0.001). The number of activated
lamina propria lymphocytes was also reduced after antibiotic treatment.
In conclusion, antibiotic therapy significantly ameliorates the
severity of ileitis in SAMP1/YitFc mice by a mechanism involving
down-regulation of activated gut lymphocytes and inhibition of
intestinal Th1 cytokine production. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To further support this theory, manipulation of intestinal flora with antibiotics, especially those against anaerobes or Gram-negative microorganisms, has been proven effective in ameliorating inflammatory bowel disease (IBD) (6, 7, 8, 9). In one study, >60% of patients with active CD experienced a clinical response following a 10-wk course of ciprofloxacin/metronidazole, independent of concomitant corticosteroid therapy (6). The same combination of antibiotics resulted in clinical remission in 45% of patients with moderately active CD (9). In other studies, macrolides in combination with rifabutin (7) and clarithromycin (8) were effective in inducing remission in severe CD. Similar results were obtained from animal studies, which showed that administration of antimicrobial agents can prevent the development of intestinal inflammation or attenuate disease severity in experimental IBD (10, 11, 12, 13). Recently, the administration of probiotic compounds has been effectively used to increase the number of potentially protective microorganisms in the intestinal lumen and control intestinal inflammation in certain clinical settings, as well as in experimental IBD (14, 15).
The mechanism(s) by which indigenous bacteria mediate intestinal inflammation have not been fully elucidated. The most accepted theory is that of a direct interaction between bacteria and bacterial products and the gut immune system. Normally, the gut immune system develops tolerance against Ags from resident intestinal bacteria (16). However, this state of hyporesponsiveness is broken in clinical and experimental IBD (16, 17). Therefore, it is possible that, in a genetically predisposed individual, intestinal bacteria gain access to the lamina propria through a disrupted epithelial barrier, thus providing a constant antigenic stimulus that leads to dysregulated activation of the gut immune system. This, in turn, triggers and perpetuates chronic intestinal inflammatory responses (18).
In recent years, various animal models of intestinal inflammation have
been described (19). Although these models provide
valuable information in specific aspects of the pathogenesis underlying
CD, they suffer from two important shortcomings. First, disease almost
uniformly develops in the large intestine, leaving the site primarily
involved in CD—the terminal ileum—unaffected. Second, the cause of
inflammation is usually a clearly defined genetic, immunologic, or
chemical intervention, highly unlikely to contribute to the human
condition. The SAMP1/YitFc mouse is a new mouse model that overcomes
these deficiencies, because it spontaneously develops chronic
intestinal inflammation, characteristically located in the terminal
ileum. The SAMP1/YitFc mouse represents a substrain developed at the
University of Virginia by continuous brother-sister mating of the
parental SAMP1/Yit strain, originally developed by S. Matsumoto
(Yakult Central Institute for Microbiological Research, Tokyo, Japan)
in Japan (20, 21). Two breeding pairs of the original
SAMP1/Yit Japanese mice were kindly provided to our group in 1996.
After >20 generations of brother-sister mating, mice in our colony
developed several phenotypic changes that justified their description
as a new murine substrain, which we have named
SAMP1/YitFc.4 The striking similarities between disease in
SAMP1/YitFc mice and CD include histological features of
transmural, discontinuous infiltration of the bowel wall with both
acute and chronic inflammatory cells, occasional formation of
granulomas, and prominent hypertrophy of the muscularis propria.
Recently, the occurrence of perianal disease was also described in our
colony.4 Ileitis in
SAMP1/YitFc mice is mediated by activated lymphocytes that heavily
infiltrate the lamina propria and have the ability to adoptively
transfer disease to MHC-matched SCID mice. (20). Moreover,
mesenteric lymph node (MLN) cells from mice with established ileitis
produce high levels of TNF and IFN-, consistent with Th1-mediated
inflammation (20). Similar to human CD, intestinal
inflammation in SAMP1/YitFc mice responds to corticosteroids and TNF
blockade. The development of ileitis in SAMP1/YitFc mice may require
the presence of intestinal bacteria, because the original SAMP1/Yit
strain did not develop inflammation when raised in a germfree
environment. Interestingly, ileitis was established when bacteria were
introduced at a later age (21).
In the present study, to further investigate the role of indigenous bacterial flora in ileitis pathogenesis in SAMP1/YitFc mice, we tested whether 1) antibiotic treatment would be effective in preventing the development and/or attenuating the severity of established inflammation in SAMP1/YitFc mice and 2) the administration of antibiotics would lead to decreased activation of the gut immune system. In this paper, we report for the first time that antibiotic therapy in a spontaneous mouse model of human CD significantly reduces the severity of ileitis by a mechanism that involves down-regulation of activated gut lymphocytes and inhibition of intestinal Th1 cytokine production.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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SAMP1/YitFc mice were maintained under specific pathogen-free conditions in the animal facility of the University of Virginia. A combination of ciprofloxacin (50 mg/kg/day) and metronidazole (100 mg/kg/day) was administered to 40-wk-old SAMP1/YitFc mice (i.e., with established ileitis) for 4 wk by addition to drinking water (treatment protocol). In a similar fashion, 3-wk-old SAMP1/YitFc mice (i.e., before the development of ileitis) were treated for 6 wk with ciprofloxacin/metronidazole immediately after weaning (prevention protocol). In a separate experiment, to evaluate any long-term effects of antibiotic treatment, 40-wk-old mice were given a 4-wk course of ciprofloxacin/metronidazole and sacrificed 6 wk after the cessation of antibiotics. In all protocols, sex-matched littermates consuming regular drinking water served as controls. Mice were allowed ad libitum access to regular or medicated water. Water consumption and animal weight were monitored daily. There were no significant differences in water consumption between antibiotic-treated and control animals. All protocols were approved by the Animal Care and Use Committee of the University of Virginia. Fecal samples from SAMP1/YitFc mice were tested by PCR and consistently found to be negative for the presence of Helicobacter hepaticus, Helicobacter bilis, and other known murine Helicobacter species.
Histological assessment of ileitis
Upon completion of prevention and treatment protocols, mice were anesthetized and sacrificed by cervical dislocation. Terminal ilea were removed, rinsed with cold PBS, rolled over a plastic pipette (Swiss-roll technique), and fixed in Bouin’s solution (LabChem, Pittsburgh, PA). H&E-stained sections were evaluated histologically by a single pathologist (C.A.M.) in a blinded fashion. A validated semiquantitative scoring system was used, as has been reported previously (22). Briefly, scores ranging from 0 (normal histology) to 3 (maximum severity of histologic changes) were used to evaluate histologic indices for 1) active inflammation (neutrophil infiltration), 2) chronic inflammation (lymphocytes, plasma cells and macrophages in the mucosa and submucosa), and 3) villous distortion (flattening and/or widening of normal villous architecture). The total inflammatory index represents the sum of the three individual indices.
Isolation of MLN and lamina propria mononuclear (LPMN) cells
MLN cells were aseptically removed at the time of sacrifice and passed through a 100-µm-cell strainer to obtain single-cell suspensions. LPMN cell isolation was performed as previously reported (20). Briefly, freshly resected terminal ilea were washed with cold HBSS and cut into 2- to 5-mm pieces. Samples were then sequentially incubated in HBSS solution containing dithioerythritol (0.145 mg/ml) and EDTA (0.37 mg/ml) at 37°C for 15 min to remove debris and epithelial cells, and further digested twice in RPMI 1640 containing 100–400 U/ml collagenase VIII (Sigma-Aldrich, St. Louis, MO) at 37°C for 60 min. Lymphocyte-enriched populations were isolated at the 40%/100% interface of a discontinuous Percoll gradient (Amersham Pharmacia Biotech, Uppsala, Sweden).
Cell culture
MLN cells were cultured either unstimulated or under stimulation with immobilized anti-CD3. To stimulate T cells, 24-well plates were incubated with 10 µg/ml of anti-CD3 Abs (BD PharMingen, San Diego, CA) for 90 min at 37°C and washed three times with PBS. MLN cells (1 x 106 cells in 1 ml medium per well) were cultured for 24 or 48 h in complete medium (RPMI 1640 with 10% FBS, 2 mM L-glutamine, and 1% penicillin/streptomycin), and supernatants were harvested for analyses.
Cytokine measurement
Total protein levels of TNF, IFN-, IL-10, and IL-4 in cell
culture supernatants were determined by commercially available ELISA
(R&D Systems, Minneapolis, MN) according to the manufacturer’s
protocol.
Flow cytometry
For the determination of cell surface activation markers, cells in suspension (106 cells per condition) were labeled by 30-min incubation with the appropriate fluorochrome-tagged Abs. Abs against CD4, CD8, CD69, CD44, CD45RB and (BD PharMingen, San Diego, CA) were used. Cells were washed with cold PBS to remove Ab excess and fixed in 1% paraformaldehyde. After gating for lymphocytes by forward and side scatter, the percentage of cells expressing surface markers and the intensity of expression were determined by single- and two-color analyses, using a FACSCalibur (BD Biosciences, San Jose, CA) and CellQuest software (BD Immunocytometry Systems, San Jose, CA).
Statistical analysis
Mean histological scores, mean number of cells expressing markers of activation, and mean cytokine levels between treated and control animals were compared using a two-sided Student t test. Data are expressed as mean ± SEM. An alpha level of 0.05 was considered significant (p < 0.05).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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At the time of weaning (week 3), there was no histological
evidence of ileitis in SAMP1/YitFc mice (data not shown). In contrast,
by week 9, ileitis was established in control animals (Fig. 1
, A and B).
SAMP1/YitFc mice, treated with ciprofloxacin/metronidazole for 6 wk,
starting from wk 3, demonstrated significantly lower total inflammatory
indices by wk 9 (6.2 ± 1.2 vs 10.3 ± 1.2 in untreated
controls, p < 0.05) (Fig. 2). Antibiotic-treated mice had
significantly lower inflammatory indices for villous distortion
(2.6 ± 0.5 vs 4.3 ± 0.5 for controls, p <
0.05), active inflammation (2.4 ± 0.5 vs 3.9 ± 0.5,
p < 0.05), and chronic inflammation (1.3 ± 0.2,
vs 2.1 ± 0.3, p < 0.05) (Fig. 2). In addition, 6
of 15 animals in the antibiotic group had very low total inflammatory
indices (i.e., 
2.5), indicating almost complete prevention of
ileitis in 40% of mice (Fig. 1, C and D).
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We next tested whether the combination of
ciprofloxacin/metronidazole could be efficient in reversing
established, long-standing chronic ileitis characteristic of 40-wk-old
SAMP1/YitFc mice (Fig. 3, A
and B). Four weeks of antibiotic treatment resulted in
significant amelioration of intestinal inflammation (total inflammatory
index: 7.7 ± 0.6 vs 10.1 ± 0.6 in controls,
p < 0.01) (Fig. 3, C and D, and
Fig. 4). The most significant decrease
was observed in the villous distortion index (3.3 ± 0.2 in the
antibiotic-treated group vs 4.3 ± 0.3 in controls,
p < 0.01). However, both chronic and active indices
were also significantly decreased in the antibiotic-treated group
(2.6 ± 0.3 vs 3.4 ± 0.3, p < 0.05, for
active inflammation, and 1.8 ± 0.2 vs 2.5 ± 0.2,
p < 0.05, for chronic inflammation) (Fig. 4). Overall,
ciprofloxacin/metronidazole administration resulted in a less
pronounced amelioration of established ileitis (25% reduction of total
inflammatory score) compared with the effects of antibiotics in
preventing the initial development of intestinal inflammation (40%
reduction of total inflammatory score). No differences were observed in
the severity of ileitis between control and
ciprofloxacin/metronidazole-treated mice, when animals were evaluated
histologically 6 wk after the cessation of antibiotics (data not
shown).
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Previous studies in SAMP1/Yit mice have shown that the
establishment of ileitis correlates with heavy infiltration of small
intestine lamina propria with CD4+ and
CD8+ lymphocytes that are overexpressing surface
markers of activation (20). Therefore, we addressed the
hypothesis that the beneficial effect of antibiotic administration is
mediated by down-regulation of the activation status of intestinal
lymphocytes. The lamina propria lymphocyte population of ilea from
9-wk-old SAMP1/YitFc mice receiving regular or medicated water was
analyzed by flow cytometry. No difference was observed in the number of
CD8+ cells, whereas amelioration of intestinal
inflammation following the administration of
ciprofloxacin/metronidazole was associated with a marked decrease in
the number of CD4+ cells infiltrating the lamina
propria (Fig. 5). Accordingly, the number
of CD4+ lymphocytes expressing the surface
activation markers CD44 and CD69 was also decreased in the
antibiotic-treated group (Fig. 5). These data indicate that,
following antibiotic administration, the number of effector
CD4+ lymphocytes that infiltrate the lamina
propria and display an immunologically activated phenotype was
decreased. In addition, a lower number of lamina propria lymphocytes
expressing the
CD4+/CD45RBhigh (naive)
phenotype was present in SAMP1/YitFc mice treated with antibiotics, as
compared with control animals (Fig. 5).
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MLN lymphocytes from inflamed SAMP1/Yit mice have been shown to
express Th1 cytokine polarization with production of high levels of
IFN- and TNF upon stimulation (20). Therefore, we
addressed the question of whether amelioration of ileitis following the
administration of antibiotics was associated with a reduced production
of proinflammatory cytokines in MLN cells. Production of IFN- and
TNF from unfractionated MLN cells was elevated at wk 9 and markedly
increased by wk 44 (Fig. 7). Preventive
administration of ciprofloxacin/metronidazole resulted in a significant
decrease of both TNF (61.5 ± 13 pg/ml vs 134 ± 19 pg/ml for
the untreated group, p < 0.01) and IFN- production
(0.53 ± 0.2 ng/ml vs 1.84 ± 0.4 ng/ml for the untreated
group, p < 0.05) (Fig. 7, upper panels).
Similarly, MLN cells from mice with established ileitis treated with
ciprofloxacin/metronidazole produced significantly lower amounts of TNF
(333 ± 11 pg/ml vs 496 ± 20 pg/ml for the untreated group,
p < 0.001) and IFN- (8.4 ± 0.4 ng/ml vs
12.4 ± 0.7 ng/ml for the untreated group, p <
0.005) (Fig. 7, upper panels). In contrast, no significant
differences were observed in the production of IL-10 and IL-4 between
antibiotic-treated and control animals, in either the prevention or
treatment protocols (Fig. 7, lower panels).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our data show that ciprofloxacin/metronidazole were more effective as
preventive therapy, with complete absence of ileitis development in a
large percentage of mice. In contrast, long-standing ileitis was more
resistant to antibiotic therapy. These data are consistent with recent
studies reporting greater success in prevention rather than treatment
of intestinal inflammation with antibiotics. In HLA-B27 transgenic
rats, neither metronidazole nor ciprofloxacin significantly ameliorated
established colitis, whereas both were effective in preventing its
development (13). Ciprofloxacin or the combination of
metronidazole/neomycin prevented the development of colitis in
IL-10 gene-deficient mice; however, after disease was
established, it was more resistant to antibiotic treatment
(11). Recently, it was reported that
ciprofloxacin/metronidazole ameliorated disease in acute
dextran-sulfate-sodium-colitis but had no effect once the
chronic phase was established (10). In our study, various
explanations may account for the resistance of ileitis to treatment, as
compared with prevention. First, our preventive protocol was started
immediately at the time that young mice were weaned. Weaning represents
a critical time for the development of gut flora in mice. Studies in
BALB/c (23) and IL-10 gene-deficient mice
(11) have clearly shown that, during weaning, the
introduction of new dietary elements leads to rapid changes in gut
microflora, especially in the small intestine (23),
including the appearance of new bacterial species (11). In
SAMP1/YitFc mice, no indication of ileitis is observed at wk 3, but
intestinal inflammation develops during the first 10 wk of age. It is
possible that alterations in bacterial flora also take place in
SAMP1/YitFc mice after weaning, and new microorganisms provide the
antigenic material responsible for initiation of the inflammatory
response. Prevention of ileitis by early antibiotic administration can
be attributed to qualitative and/or quantitative changes in the
composition of this pathogenic indigenous flora. The possibility that
food-derived Ags trigger gut immune responses after weaning is not
supported by the absence of ileitis in germ-free SAMP1/Yit mice
(21). Second, the reduced effects of antibiotic treatment
in established ileitis may be related to the augmented Th1 response in
older animals, as indicated by the dramatic increase in IFN- and TNF
production from MLN cells. Therefore, it is unlikely that antibacterial
therapy alone is sufficient to down-regulate the activation of
intestinal lymphocytes in established ileitis. Combining antimicrobial
therapy with anti-Th1 cytokine blockade may prove more effective in
treating established ileitis in CD. Finally, ileitis per se seems to be
more resistant to antibiotic therapy, in comparison to colitis. This is
supported by reports that patients with CD-colitis benefit more from
antibiotics than patients with small bowel involvement (6, 24). In addition, mice with experimental colitis show a better
response to antibiotics than the response seen in the present study.
Because bacterial counts are higher in colon than ileum and the
distribution of microorganisms is similar, this resistance of ileitis,
as compared with colitis, cannot be easily attributed to differences in
the bacterial flora. Most likely it relates to the fact that the gut
immune system is more affluent in the distal part of the small
intestine than in the colon. Therefore, it is possible that immunologic
activation in the terminal ileum can be sustained with lower levels of
bacterial load.
The mechanism(s) by which indigenous microflora trigger clinical and
experimental IBD are not fully understood. Recent studies in patients
with CD and animal models of colitis show a direct association between
bacterial Ags and activation of gut lymphocytes. Mucosal Abs against
intestinal bacteria have been described in patients with IBD
(25). Duchmann et al. (16) reported that
tolerance normally exists toward autologous intestinal flora but is
abrogated in active CD. Similarly, in the trinitrobenzene sulfonic
acid model of colitis, induction of intestinal inflammation is
associated with loss of tolerance against normal intestinal bacteria
(26). Finally, CD4+ MLN lymphocytes
from spontaneously colitic C3H/HeJBir mice proliferate and secrete Th1
cytokines upon stimulation with cecal bacterial sonicates
(27). Several findings from our study indicate that, in
SAMP1/YitFc mice, suppression of bacterial flora with antibiotics
down-regulates the gut immune system. First, in the lamina propria
compartment, we observed a decrease in the number of
CD4+ lymphocytes and, accordingly, in the number
of CD4+ lymphocytes expressing the activation
markers CD44 and CD69. These results are consistent with a reduction in
the number of effector cells after antimicrobial treatment. Second, the
decreased cellularity in the MLN supports the concept of decreased
recruitment and/or proliferation of gut immune cells following
suppression of intestinal bacterial load. Third, we observed a
significant reduction in IFN- and TNF production by MLN cells
following ciprofloxacin/metronidazole treatment. We have previously
shown that ileitis in SAMP1/YitFc mice is characterized by increased
production of IFN- and TNF from MLN cells (20). The
suppression of Th1 cytokines by antimicrobial treatment
raisesthe possibility that antigenic stimuli originating from
intestinal bacteria are responsible for intestinal Th1 polarization in
SAMP1/YitFc mice.
An interesting immunologic finding in our study is the decrease in the
number of CD4+/CD45RBhigh
lymphocytes after antibiotic treatment, both in the lamina propria and
MLNs. Previous studies have shown that
CD4+/CD45RBhigh cells
produce high levels of IFN- upon stimulation and induce an IBD-like
colitis when they are adoptively transferred into SCID mice
(28). Of note, in the
CD4+/CD45RBhigh transfer
model of colitis, CD4+ lymphocytes from SCID mice
with intestinal inflammation proliferate and produce Th1 cytokines upon
stimulation with bacterial sonicates (29). In addition,
intestinal disease is ameliorated after antibiotic administration
(30). The observed decrease in
CD4+/CD45RBhigh lymphocytes
in both the lamina propria and MLNs of antibiotic-treated mice
indicates that this lymphocyte subpopulation may also play an important
role in the SAMP1/YitFc mouse model of ileitis.
Recent studies have proposed specific associations between defined bacterial species and intestinal inflammation in animal models of IBD. Rath et al. (31) have clearly shown that Bacteroides vulgatus is capable of inducing colitis in HLA-B27 transgenic rats. However, a recent publication from the same group reported that ciprofloxacin prevented the development of colitis in this model without affecting the number of colonic Bacteroides species and that the broad-spectrum vancomycin/imipenem treatment was more effective than metronidazole alone in disease attenuation (13). Similarly, in IL-10-deficient mice, Enterococcus faecalis has been proposed as an important pathogen for the development of colitis (32). However, treatment with metronidazole/neomycin resulted in prevention and treatment of colitis despite the fact that the number of adherent or translocated Enterococcus species was actually increased (11). These results indicate that, although the role of well-defined microorganisms may be important in certain animal models of IBD, the primary mechanism of action of antibiotics appears to be the ability to suppress the overall intestinal bacterial load. This can also explain results from human studies where antibiotics with diverse antimicrobial spectra have proven to be effective in ameliorating intestinal inflammation in CD (7, 8, 33). The combination of ciprofloxacin/metronidazole, used in our study, provides a wide antimicrobial spectrum that covers the majority of microorganisms in the bowel lumen, namely anaerobes and Gram-negative bacteria. Our results cannot discriminate whether the effects of antibiotics were mediated by a decrease in total bacterial counts or by suppression of specific bacterial species. Preliminary data from our group support the former, because administration of either ciprofloxacin or metronidazole as single therapies was capable of attenuating the severity of ileitis in SAMP1/YitFc mice (our unpublished data). The lack of significant histological differences between antibiotic-treated and control animals 6 wk after cessation of treatment indicates that constant suppression of the intestinal bacterial load is needed to maintain the anti-inflammatory effect. Recently, immunomodulating properties have been proposed for both metronidazole (34) and ciprofloxacin (35). These effects cannot be excluded in our study. However, studies in other models have shown that, in doses equal to or higher than the ones used in our protocols, ciprofloxacin and metronidazole exert their actions mainly through their antibacterial properties (11).
The results of our study could have important implications for the
management of CD. Contrary to all other models of IBD that uniformly
develop colitis, the SAMP1/YitFc mouse spontaneously develops
intestinal inflammation that, as in the majority of CD cases, is
localized to the terminal ileum. Thus, this model most closely
resembles the human condition and offers the opportunity to study the
effects and mechanisms of action of antibiotics on small intestinal
inflammation. The intriguing possibility exists that common
bacterial-derived Ags trigger the dysregulated immune response seen in
both SAMP1/YitFc mice and CD. To our knowledge, this is the first
animal study describing the ability of antibiotics to ameliorate small
intestinal inflammation and down-regulate the activation of intestinal
lymphocytes, as well the production of proinflammatory Th1 cytokines,
such as IFN- and TNF. Interestingly, the first gene shown to be
clearly associated with a genetic predisposition to CD (i.e.,
NOD2) is a member of a family of genes implicated in sensing
bacteria in the gastrointestinal lumen (36, 37). With
an increased understanding of genetic predisposition to IBD,
genetically susceptible individuals could be protected from disease
development with the appropriate manipulation of bacterial flora at an
early time point. Of note, metronidazole was effective in preventing
the postoperative relapse of CD one year after ileal resection
(38). Moreover, antibiotics can be used as first-line
therapy with the goal of decreasing the antigenic load and
down-regulating the gut immune system, potentially augmenting the
efficacy of other immunomodulatory therapies for CD. The recent
unsatisfactory results of IL-10 treatment in CD (39)
suggest that such combination therapies may offer a therapeutic
advantage as compared with single-agent treatments.
In conclusion, ileitis in SAMP1/YitFc mice can be prevented and treated with the administration of broad-spectrum antibiotics. Antibiotic administration down-regulates the activity of intestinal immune cells, suggesting that intestinal inflammation in the SAMP1/YitFc mice is mediated by a dysregulated immune response against resident intestinal bacteria.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Fabio Cominelli, Digestive Health Center of Excellence, University of Virginia Health System, P.O. Box 800708, Charlottesville, VA 22908. E-mail address: fc4q{at}virginia.edu
3 Abbreviations used in this paper: CD, Crohn’s disease; IBD, inflammatory bowel disease; LPMN, lamina propria mononuclear cells; MLN, mesenteric lymph node.
4 J. Rivera-Nieves, G. Bamias, A. Vidrich, M. Marini, T. T. Pizarro, M. J. McDuffie, S. Cohn, C. A. Moskaluk, and F. Cominelli. Emergence of perianal fistulizing disease in the SAMP1/YitFc mouse, a spontaneous model of chronic ileitis. Submitted for publication.
Received for publication July 3, 2002. Accepted for publication August 27, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-deficient mice fail to develop colitis in the absence of a microbial environment. Am. J. Pathol. 150:91.[Abstract]
2-microglobulin transgenic rats. J. Clin. Invest. 98:945.[Medline]
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