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. 2004 Feb;72(2):1004–1009. doi: 10.1128/IAI.72.2.1004-1009.2004

Mucosal Vaccination Increases Endothelial Expression of Mucosal Addressin Cell Adhesion Molecule 1 in the Human Gastrointestinal Tract

Catharina Lindholm 1,*, Andrew Naylor 2, Eva-Liz Johansson 1, Marianne Quiding-Järbrink 1
PMCID: PMC321597  PMID: 14742547

Abstract

Homing of leukocytes to various tissues is dependent on the interaction between homing receptors on leukocytes and their ligands, addressins, on endothelial cells. Mucosal immunization results in homing of antigen-specific lymphocytes back to the mucosa where they first encountered the antigen. However, it is unknown whether this homing of antigen-specific cells is mediated by an altered endothelial addressin expression after vaccination. Using different immunization routes with an oral cholera vaccine, we show that the endothelial expression of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) is increased in the gastric and upper small intestinal mucosae after immunization through various local routes in the upper gastrointestinal tract. In contrast, rectal immunization did not influence the levels of MAdCAM-1 in the gastric or duodenal mucosa. Furthermore, we show that MAdCAM-1 can be induced on human endothelial cells by tumor necrosis factor alpha (TNF-α) and gamma interferon. The vaccine component cholera toxin B subunit (CTB) increased MAdCAM-1 expression on endothelial cells in cultured human gastric explants, an effect that seemed to be mediated by TNF-α. In conclusion, MAdCAM-1 expression is increased in the upper gastrointestinal tract after local immunizations with a vaccine containing CTB. This strongly suggests the involvement of MAdCAM-1 in the preferential homing of mucosal lymphocytes to their original site of activation.

Lymphocyte trafficking through secondary lymphoid and nonlymphoid tissues serves both to ensure contact of naive and memory cells with antigen and to distribute effector lymphocytes to their target tissues. Lymphocyte migration is far from random but varies with lymphocyte lineage and activation stage. In addition, memory and effector lymphocytes tend to home back to their original site of activation (4, 19, 32). This organ-specific lymphocyte homing is dependent on the expression of tissue-specific adhesion molecules on both the circulating lymphocytes and the specialized endothelial cells, i.e., high endothelial venules, in the tissue, through which most lymphocyte extravasation takes place. Homing to the gastrointestinal mucosa is mediated by lymphocyte expression of integrin α4β7, which binds to the mucosal addressin cell adhesion molecule 1 (MAdCAM-1) (1, 12). MAdCAM-1 is selectively expressed by endothelial cells in the gastrointestinal tract and in mesenteric lymph nodes, with expression seen on high endothelial venules in Peyer's patches as well as on small venules in the lamina propria in gastric and intestinal mucosae (2, 5). The expression of MAdCAM-1 on mouse endothelial cells has been shown to be upregulated by tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ) (21, 23, 31). However, whether these cytokines also are involved in the regulation of MAdCAM-1 expression on human endothelial cells is not known.

In addition to adhesion molecules, chemokines and their ligands are important for the homing of lymphocytes. Recent studies have demonstrated that the chemokine receptor CCR9 is specifically expressed on a subset of gut-homing T cells expressing α4β7 and that its ligand thymus-expressed chemokine (TECK) is produced in the small intestine (16, 37). In addition, human immunoglobulin A (IgA)-secreting B cells from most organs express CCR10 and migrate toward its ligand mucosa-associated epithelial chemokine (MEC) (17). Endothelial cells in many inflamed tissues increase their expression of vascular cellular adhesion molecule 1 (VCAM-1), which contributes to recruitment of lymphocytes expressing integrin α4β1 (6).

We and others have previously shown that circulating B and T cells activated by mucosal immunization or infection carry the mucosal homing receptor α4β7 (14, 15, 27, 29, 30, 34) and home back to mucosal tissues. During the last few years it has also become evident that there is a certain degree of compartmentalization within the mucosal immune system, in the sense that effector B cells home to the specific part of the gut where they first encountered the antigen (7, 8, 26). These regional immune responses cannot be explained only by α4β7 expression, since virtually all circulating B cells induced by oral, rectal, or nasal antigen delivery express α4β7 (27). The mechanisms behind the compartmentalization of mucosal immune responses are not well characterized but could involve differences in chemokine production (16) or differential regulation of endothelial adhesion molecules. In this study, we examined whether local or distant mucosal immunizations could influence the endothelial expression of MAdCAM-1, VCAM-1, and E-selectin in the upper gastrointestinal tract. Furthermore, the role of TNF-α and IFN-γ in the regulation of MAdCAM-1 expression on human endothelial cells was evaluated.

MATERIALS AND METHODS

Subjects.

This study was approved by the Human Research Ethical Committee of the Medical Faculty, Göteborg University, and the Medical Products Agency and was performed after informed consent was given by all of the volunteers.

Twenty-three Helicobacter pylori-infected subjects were recruited among patients referred for gastroduodenal endoscopy at the Sahlgrenska University Hospital, Göteborg, Sweden, or by serological screening of healthy blood donors (9). H. pylori infection was diagnosed by positive serology or urea breath test and was confirmed by positive culture of biopsies. None of the volunteers had taken any medication for at least 1 week before the study. In addition, eight uninfected healthy Swedish adult volunteers were recruited. Gastric mucosa was also obtained from four patients undergoing gastrectomy due to gastric adenocarcinoma. Normal gastric mucosa was obtained from sites at least 5 cm from the tumor tissue.

Vaccination protocols and specimen collection.

All volunteers received two doses of an oral cholera vaccine (Dukoral; SBL Vaccin, Stockholm, Sweden) (11) 2 weeks apart. Each dose of the vaccine consisted of 1 mg of recombinantely produced cholera toxin B subunit (CTB) and 1011 formalin-inactivated Vibrio cholerae bacteria. Eight of the volunteers (two women and six men; mean age, 45 years [range, 36 to 61 years]) were given the vaccine twice intragastrically after 36 h of antisecretory treatment as described previously (28). Briefly, 4 ml of the vaccine was given through the endoscope as droplets on the gastric antral mucosa with the patient in the left-side position.

Another group of H. pylori-infected subjects (four women and four men; mean age, 46 years [range, 33 to 58 years]) were given the vaccine twice in the small intestine as previously described (28). In short, the vaccine was distributed in a volume of 20 ml through the endoscope at the level of the ligament of Treitz', i.e., 30 cm distal of the pyloric sphincter.

Seven additional H. pylori-infected subjects (one woman and six men; mean age, 45 years [range, 21 to 57 years]) were given the vaccine rectally in a volume of 1 ml.

In addition, eight healthy uninfected volunteers (three women and five men; mean age, 28 years [range, 21 to 35 years]) received two doses of the vaccine, mixed in sodium bicarbonate to a final volume of 150 ml, orally.

Gastroduodenal endoscopies were performed before and 1 week after the last immunization of each subject, and biopsies were collected from the antral and duodenal mucosae at both time points from all subjects. Biopsies for immunohistochemical analysis were embedded in O.C.T. compound (Tissue Tek) and frozen in liquid nitrogen.

The putative impact of immunization on the density of blood vessels in the human gastrointestinal mucosa was studied by immunohistochemical detection of von Willebrand factor, as a general endothelial cell marker. The von Willebrand factor-positive blood vessels constituted approximately 2% of the total area of both gastric and duodenal tissue sections and were not influenced by the various immunization routes. In addition, the endothelial von Willebrand factor expression was similar in the different study groups.

Culture of gastric explants.

Gastric mucosal explants were prepared as previously described (18) from resected noncancerous tissue from the antra of patients undergoing gastrectomy. In short, the mucosal layer was cut from underlying muscle layers, and pieces with a diameter of 3 mm were punched out and put in culture dishes with Iscove's complete medium supplemented with 5% (vol/vol) fetal calf serum and 100 μg of gentamicin per ml. The explants were then stimulated by addition of 200 ng of TNF-α per ml, 500 ng of IFN-γ per ml, 100 or 500 μg of CTB per ml, or the Dukoral vaccine diluted 1:4, 1:10, 1:20, or 1:100 to the culture medium. An anti-human TNF-α antibody (clone MAb1; BD PharMingen) was used in blocking experiments at a final concentration of 100 ng/ml. Tissue samples were snap frozen, and culture medium was collected after 18 and 24 h of culture.

Immunohistochemical detection of endothelial addressins.

The endothelial expression of MAdCAM-1, VCAM-1, and E-selectin was determined by immunohistochemistry. After blocking of endogenous peroxidase activity with 0.3% H2O2 in phosphate-buffered saline (PBS), cryo-cut tissue sections from biopsies or gastric explants were incubated with monoclonal antibodies against MAdCAM-1 (a kind gift from Leukocyte USA), VCAM-1, E-selectin, or von Willebrand factor (all from DAKO, Glostrup, Denmark) at optimal dilutions in PBS with 5% human AB serum for 60 min at room temperature. The reaction was developed by stepwise addition of horseradish peroxidase-conjugated rabbit anti-mouse IgG (DAKO), 3,3-diaminobenzidine, and H2O2. Counterstaining was performed with Mayer′s hematoxylin. An irrelevant isotype-matched antibody (DAKO) was included in each experiment as a negative control and never gave any staining. The entire tissue sections, cut to similar depths, were examined in a light microscope, and the percentage of the specifically stained area in each section was determined by using Leica Qwin software. To determine the variation of MAdCAM-1 expression in different regions of the antrum and duodenum of the same subject, three different biopsies were sampled from the antra and the duodena of three individuals. This evaluation was done separately in biopsies obtained both before and after immunization and showed that the MAdCAM-1 expression never varied by more than 0.1% in the antrum and by more than 0.18% in the duodenum. In addition, the MAdCAM-1 expression in different sections, cut to the same depths, of the same biopsy was evaluated and showed little variation.

Addressin expression on HUVEC.

Cultured human umbilical cord endothelial cells (HUVEC) were purchased from Cascade Biologies Inc. and were cultured as previously described (13) in M200 medium supplemented with low-serum growth supplement (Cascade Biologies Inc.). HUVEC in passage 4 to 7 were grown to confluence in chamber slides (Falcon, Becton Dickinson Labware Europe) and stimulated with CTB at 1, 10, or 100 μg/ml; Dukoral diluted 1:4 and 1:20; TNF-α at 200 ng/ml; or IFN-γ at 500 ng/ml for 5, 20, or 28 h. After fixation with acetone, the cells were incubated overnight at 4°C with anti-MAdCAM-1 antibody diluted 1:10 in PBS, followed by incubation for 3 h at room temperature with fluorescein isothiocyanate-conjugated F(ab′)2 fragments of rat anti-mouse IgG (Dakopatts, Alvsjö, Sweden). Propidium iodide (Sigma) was added and left briefly for contrast nuclear staining. After mounting, the slides were examined in a Leica microscope.

Statistical analyses.

Comparisons of addressin expression before and after vaccination within each study group were made by the Wilcoxon matched pairs test. P values of <0.05 were regarded as indicating significant differences.

RESULTS

Immunization in the upper gastrointestinal tract increases the endothelial expression of MAdCAM-1 in the gastroduodenal mucosa.

The role of endothelial cells in homing of antigen-specific lymphocytes back to their original site of antigen encounter after mucosal immunization is largely unknown. Therefore, an oral cholera vaccine consisting of killed vibrios and the nontoxic CTB was given by the oral, gastric, jejunal, or rectal route for evaluation of the impact of local and distant mucosal immunizations on the endothelial expression of MAdCAM-1, VCAM-1, and E-selectin in the gastrointestinal tract.

MAdCAM-1 expression was significantly increased in the duodenal mucosa after upper gastrointestinal tract immunizations, i.e., after jejunal, gastric, or oral vaccination (Fig. 1 and 2E and F).

FIG. 1.

FIG. 1.

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MAdCAM-1 expression in duodenum before and after immunization. Duodenal biopsies were obtained before and after jejunal, intragastric, oral, or rectal immunization of the volunteers. Sections were analyzed by immunohistochemistry, and the MAdCAM-1-specifically stained area was determined and is given as the percentage of the total area of the tissue section. **, P < 0.01; *, P < 0.05.

FIG.2.

FIG.2.

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Photomicrographs showing MAdCAM-1 as detected by immunofluorescence (A and B) and by immunohistochemistry (C to F). (A) Lack of MAdCAM-1 expression on unstimulated HUVEC. (B) Induction of MAdCAM-1 expression (fluorescein isothiocyanate staining) on HUVEC after stimulation with TNF-α for 20 h. (C and D) MAdCAM-1-positive blood vessels in the stomach of a subject not infected with H. pylori before (C) and 1 week after (D) the last immunization of the same volunteer. (E and F) MAdCAM-1-specific staining in the duodenum of an H. pylori-infected subject before (E) and 1 week after (F) the last immunization of the same volunteer. Magnifications ×400 (A and B) and ×200 (C to F).

Jejunal administration of the vaccine increased the MAdCAM-1 expression in the duodena of all of the subjects (eight of eight; P < 0.01), whereas gastric and oral administration increased the duodenal MAdCAM-1 expression in seven out of eight volunteers (P < 0.05). In contrast, the expression of MAdCAM-1 in the duodenal mucosa was not influenced by distant, i.e., rectal, immunization (Fig. 1).

Gastric, jejunal, and oral administration of the vaccine also significantly increased the proportion of MAdCAM-1-positive endothelium in the stomach (P < 0.05) in the majority of the subjects (Fig. 3 and 2C and D). This effect was seen both in individuals with gastric inflammation caused by H. pylori infection and in uninfected subjects. As in the duodenum, rectal immunization had no impact on the gastric MAdCAM-1 levels.

FIG. 3.

FIG. 3.

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MAdCAM-1 expression in the stomach before and after immunization. Antral biopsies were obtained before and after jejunal, intragastric, oral, or rectal immunization of the volunteers. Sections were analyzed by immunohistochemistry, and the MAdCAM-1-specifically stained area was determined and is given as the percentage of the total area of the tissue section. *, P < 0.05.

In contrast to MAdCAM-1, E-selectin, which was expressed at low levels in the majority of the biopsies, was not affected by any of the immunization routes. The average stained area was 0.2% in the antrum and 0.08% in the duodenum, both before and after the immunizations. Furthermore, VCAM-1-positive vessels could not be observed before or after immunization by the different immunization routes in any of the volunteers.

TNF-α and IFN-γ upregulate MAdCAM-1 expression on human endothelial cells.

Excluding changes in vessel density, the increased MAdCAM-1 expression after local immunization could be due to either a direct effect of vaccine components on the endothelial cells or an indirect effect via different tissue factors such as cytokines. We first assessed whether the vaccine or its components could induce MAdCAM-1 on endothelial cells in cultured human gastric tissue. The whole-cell vaccine as well as CTB alone increased MAdCAM-1 expression on the endothelial cells in the cultured gastric explants (Fig. 4). To directly assess the effect of the vaccine components on endothelial cells, cultured HUVEC were used as an in vitro model of mucosal endothelial cells, since these cells have the ability to express MAdCAM-1 upon stimulation (unpublished data). However, neither the vaccine nor CTB could induce MAdCAM-1 expression on HUVEC, suggesting that the vaccine-induced MAdCAM-1 upregulation in mucosal explants may be an indirect effect mediated by factors produced in the tissue, e.g., cytokines or chemokines. Since MAdCAM-1 expression on mouse endothelium is induced by IFN-γ and TNF-α both in vitro and in vivo (21, 23, 31), we examined whether these cytokines were also involved in the regulation of MAdCAM-1 expression on human endothelial cells.

FIG. 4.

FIG. 4.

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Increased expression of MAdCAM-1 in cultured gastric tissue after cytokine and vaccine stimulation. Mucosal explants from gastric tissue were cultured and stimulated with the Dukoral vaccine, CTB, TNF-α, or IFN-γ for 18 h. MAdCAM-1 expression was determined by immunohistochemical staining of tissue sections, and the specifically stained area was determined. Arithmetic means ± standard deviations from three experiments using tissue from three different donors are shown. Unstim., unstimulated.

Indeed, both IFN-γ and TNF-α increased MAdCAM-1 expression on endothelial cells in cultured human stomach explants (Fig. 4), and TNF-α induced de novo MAdCAM-1 expression on cultured HUVEC (Fig. 2B). Enzyme-linked immunosorbent assay analyses of culture medium from stimulated explants showed that CTB induced secretion of TNF-α, with the concentration increasing from <15.6 to 50.2 ± 12.1 pg/ml after 24 h of stimulation. The finding that the CTB effect on MAdCAM-1 expression on endothelial cells in cultured gastric explants could be almost completely blocked by addition of a TNF-α-specific neutralizing antibody further indicates that the CTB effect on MAdCAM-1 expression indeed is mediated by TNF-α. In contrast, CTB did not induce IFN-γ production, probably because the cultured mucosal tissue contained very few IFN-γ-producing cells, e.g., T and natural killer cells.

DISCUSSION

Mucosal immunization results in homing of antigen-specific lymphocytes back to the mucosal tissue where they first encountered the antigen. Whereas the impact of immunization on the expression of mucosal homing receptors on circulating lymphocytes has been rather well studied (15, 27), it is unknown whether this homing of specific cells is mediated by an altered endothelial addressin expression after vaccination. In the present study we show that the endothelial expression of MAdCAM-1 is increased in the gastric and upper small intestinal mucosae after immunization by various local routes with an oral cholera vaccine in the upper gastrointestinal tract.

It is likely that the increased MAdCAM-1 expression in the mucosa after immunization is one of the mechanisms controlling the recruitment of vaccine-specific lymphocytes back to the site of antigen encounter. This is further supported by our finding that rectal immunization did not influence the levels of MAdCAM-1 in the gastric or duodenal mucosa. Furthermore, the finding of increased MAdCAM-1 levels only in the mucosa close to the inductive site provides an explanation for the previously demonstrated compartmentalization of mucosal immune responses (7, 8, 26). This notion is also supported by the fact that only jejunal, gastric, and oral immunizations result in specific B-cell migration into the duodenal and gastric mucosae in H. pylori-infected subjects (28), whereas rectal immunization does not (unpublished data). We have previously shown that H. pylori infection per se does not alter the expression of MAdCAM-1 on gastric endothelial cells (28) and the immunization-induced upregulation of MAdCAM-1 in the stomach was independent of H. pylori status. Nevertheless, our previous studies clearly demonstrate that migration of antibody-secreting cells induced by oral immunization into the gastric mucosa is achieved only in H. pylori-infected subjects (20, 28). Therefore, in addition to increased MAdCAM-1 expression, additional signals, such as chemokines, are probably involved in attracting homing lymphocytes to distinct parts of the gastrointestinal mucosa. TECK, for example, is produced almost exclusively in the small intestine (16, 36). In addition, the CXCR3 and CXCR4 ligands have recently been shown to recruit circulating plasmablasts induced by intraperitoneal immunization (10). With regard to H. pylori infection, the IFN-γ-inducible CXCR3 ligands I-TAC, Mig, and IP-10 might well contribute to antibody-secreting cell recruitment to the inflamed gastric mucosa. Indeed, chemokines may even enhance lymphocyte binding to MAdCAM-1 (22, 35). Nevertheless, endothelial expression of MAdCAM-1 is likely a prerequisite for the subsequent action of chemokines in the recruitment of lymphocytes. In the present study we found that the vaccine component CTB as well as the whole vaccine increased MAdCAM-1 expression on endothelial cells in cultured human gastric explants but not on cultured human endothelial cells. We speculated that the vaccine-induced MAdCAM-1 expression could be mediated by tissue factors such as cytokines, which have been shown to induce MAdCAM-1 expression on mouse endothelial cells both in vitro and in vivo (21, 23, 31). Indeed, TNF-α, and also IFN-γ, induced de novo expression of MAdCAM-1 on cultured human endothelial cells, and the vaccine as well as CTB was found to stimulate TNF-α secretion from gastric explants. It is thus likely that the vaccine-induced MAdCAM-1 expression might be mediated by increased local production of TNF-α, which is further supported by our finding that the CTB-induced upregulation of MAdCAM-1 expression on endothelial cells in cultured gastric explants could be inhibited with a TNF-α-neutralizing antibody. However, CTB was recently reported to decrease lipopolysaccharide-induced TNF-α secretion from human macrophages (3) and has previously been shown to downregulate Th1 responses by induction of transforming growth factor β-secreting cells in various murine models (24, 33). On the other hand, the CTB-whole-cell vaccine induces Th1 cytokine responses in vivo in humans (25), and these responses might well contribute to upregulation of endothelial MAdCAM-1 expression.

In conclusion, we have shown that mucosal immunization of human volunteers with an oral cholera vaccine containing CTB results in an upregulation of MAdCAM-1 expression close to the inductive site. This strongly suggests the involvement of MAdCAM-1 in the preferential homing of mucosal lymphocytes to their original site of activation and suggests that the mucosal homing of antigen-specific lymphocytes after vaccination is dependent on a regionally increased expression of the addressin. Furthermore, our results indicate that TNF-α mediates vaccine-induced MAdCAM-1 expression in the human gastrointestinal mucosa.

Acknowledgments

We thank all of the volunteers for participating in the study, the staff at the Gastroenterology Unit at Sahlgrenska University Hospital for excellent technical assistance, and Hans Lönroth for invaluable help with biopsy sampling. We also thank Mikael Innocenti for help with HUVEC culture.

This study was financially supported by the Swedish Research Council, the Swedish Medical Society, and Magnus Bergvalls stiftelse.

Editor: F. C. Fang

REFERENCES

  • 1.Berlin, C., E. L. Berg, M. J. Briskin, D. P. Andrew, P. J. Kilshaw, B. Holzmann, I. L. Weissman, A. Hamann, and E. C. Butcher. 1993. α4β7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell 74:185-195. [DOI] [PubMed] [Google Scholar]
  • 2.Briskin, M., D. Winsor-Hines, A. Shyjan, N. Cochran, S. Bloom, J. Wilson, L. M. McEvoy, E. C. Butcher, N. Kassam, C. R. Mackay, W. Newman, and D. J. Ringler. 1997. Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissues. Am. J. Pathol. 151:97-110. [PMC free article] [PubMed] [Google Scholar]
  • 3.Burkart, V., Y. E. Kim, B. Hartmann, I. Ghiea, U. Syldath, M. Kauer, W. Fingberg, P. Hanifi-Moghaddam, S. Muller, and H. Kolb. 2002. Cholera toxin B pretreatment of macrophages and monocytes diminishes their proinflammatory responsiveness to lipopolysaccharide. J. Immunol. 168:1730-1737. [DOI] [PubMed] [Google Scholar]
  • 4.Butcher, E. C., and L. J. Picker. 1996. Lymphocyte homing and homeostasis. Science 272:60-66. [DOI] [PubMed] [Google Scholar]
  • 5.Dogan, A., M. Du, A. Koulis, M. J. Briskin, and P. G. Isaacson. 1997. Expression of lymphocyte homing receptors and vascular addressins in low-grade gastric B-cell lymphomas of mucosa-associated lymphoid tissue. 151:1361-1369. [PMC free article] [PubMed]
  • 6.Elices, M. J., L. Osborn, Y. Takada, C. Crouse, S. Luhowskyj, M. Hemler, and R. R. Lobb. 1990. VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA-4 at a site distinct from the VLA-4/fibronectin binding site. Cell 60:577-584. [DOI] [PubMed] [Google Scholar]
  • 7.Eriksson, K., M. Quiding-Järbrink, J. Osek, Å. Möller, S. Björk, J. Holmgren, and C. Czerkinsky. 1998. Specific-antibody-secreting cells in the rectums and genital tracts of nonhuman primates following vaccination. Infect. Immun. 66:5889-5896. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Eriksson, K., M. Quiding-Järbrink, J. Osek, Å. Möller, S. Björk, M. P. Kieny, J. Holmgren, and C. Czerkinsky. 1999. Anatomical segmentation of the intestinal immune response in nonhuman primates: oral and rectal immunization induce differential homing of B cells to sites defined by their source of vascularization. Infect. Immun. 67:6210-6212. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Hamlet, A. K., K. I. Erlandsson, L. Olbe, A. M. Svennerholm, V. E. Backman, and A. B. Pettersson. 1995. A simple, rapid, and highly reliable capsule-based 14C urea breath test for diagnosis of Helicobacter pylori infection. Scand. J. Gastroenterol. 30:1058-1063. [DOI] [PubMed] [Google Scholar]
  • 10.Hauser, A. E., G. F. Debes, S. Arce, G. Cassese, A. Hamann, A. Radbruch, and R. A. Manz. 2002. Chemotactic responsiveness toward ligands for CXCR3 and CXCR4 is regulated on plasma blasts during the time course of a memory immune response. J. Immunol. 169:1277-1282. [DOI] [PubMed] [Google Scholar]
  • 11.Holmgren, J., A. M. Svennerholm, M. Jertborn, J. Clements, D. A. Sack, R. Salenstedt, and H. Wigzell. 1992. An oral B subunit: whole cell vaccine against cholera. Vaccine 10:911-914. [DOI] [PubMed] [Google Scholar]
  • 12.Hu, M. C.-T., D. T. Crowe, I. L. Weissman, and B. Holzmann. 1992. Cloning and expression of mouse integrin βp (β7): a functional role in Peyer's patch-specific lymphocyte homing. Proc. Natl. Acad. Sci. USA 89:8254-8258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Innocenti, M., A. C. Thoreson, R. L. Ferrero, E. Strömberg, I. Bölin, L. Eriksson, A. M. Svennerholm, and M. Quiding-Jarbrink. 2002. Helicobacter pylori-induced activation of human endothelial cells. Infect. Immun. 70:4581-4590. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Kantele, J. M., H. Arvilommi, S. Kontiainen, M. Salmi, S. Jalkanen, E. Savilahti, M. Westerholm, and A. Kantele. 1996. Mucosally activated circulating human B cells in diarrhoea express homing receptors directing them back to the gut. Gastroenterology 110:1061-1067. [DOI] [PubMed] [Google Scholar]
  • 15.Kantele, A., J. Zivny, M. Häkkinen, C. O. Elson, and J. Mestecky. 1999. Differential homing commitments of antigen-specific T cells after oral or parenteral immunization in humans. J. Immunol. 162:5173-5177. [PubMed] [Google Scholar]
  • 16.Kunkel, E. J., J. J. Campbell, G. Haraldsen, J. Pan, J. Boisvert, A. I. Roberts, E. C. Ebert, M. A. Vierra, S. B. Goodman, M. C. Genovese, A. J. Wardlaw, H. B. Greenberg, C. M. Parker, E. C. Butcher, D. P. Andrew, and W. W. Agace. 2000. Lymphocyte CC chemokine receptor 9 and epithelial thymus-expressed chemokine (TECK) expression distinguish the small intestinal immune compartment: epithelial expression of tissue-specific chemokines as an organizing principle in regional immunity. J. Exp. Med. 192:761-768. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Kunkel, E. J., C. H. Kim, N. H. Lazarus, M. A. Vierra, D. Soler, E. P. Bowman, and E. C. Butcher. 2003. CCR10 expression is a common feature of circulating and mucosal epithelial tissue IgA Ab-secreting cells. J. Clin. Investig. 111:1001-1010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Lindholm, C., M. Quiding-Järbrink, H. Lönroth, and A. M. Svennerholm. 2001. Induction of chemokine and cytokine responses by Helicobacter pylori in human stomach explants. Scand. J. Gastroenterol. 36:1022-1029. [DOI] [PubMed] [Google Scholar]
  • 19.Mackay, C. R., W. L. Marston, and L. Dudler. 1990. Naive and memory T cells show distinct pathways of lymphocyte recirculation. J. Exp. Med. 171:801-817. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Mattsson, A., H. Lönroth, M. Quiding-Järbrink, and A. M. Svennerholm. 1998. Induction of B cell responses in the stomach of Helicobacter pylori-infected subjects after oral cholera vaccination. J. Clin. Investig. 102:51-56. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Oshima, T., P. Jordan, M. B. Grisham, J. S. Alexander, M. Jennings, M. Sasaki, and K. Manas. 2001. TNF-alpha induced endothelial MAdCAM-1 expression is regulated by exogenous, not endogenous nitric oxide. BMC Gastroenterol. 1:5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Pachynski, R. K., S. W. Wu, M. D. Gunn, and D. J. Erle. 1998. Secondary lymphoid-tissue chemokine (SLC) stimulates integrin alpha 4 beta 7-mediated adhesion of lymphocytes to mucosal addressin cell adhesion molecule-1 (MAdCAM-1) under flow. J. Immunol. 161:952-956. [PubMed] [Google Scholar]
  • 23.Parr, M. N., and E. L. Parr. 2000. Interferon-gamma up-regulates intercellular adhesion molecule-1 and vascular adhesion molecule-1 and recruits lymphocytes into the vagina of immune mice challenged with herpes simplex virus-2. Immunology 99:540-545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Ploix, C., I Bergerot, A. Durand, C., Czerkinsky, J. Holmgren, and C. Thivolet. 1999. Oral administration of cholera toxin B-insulin conjugates protects NOD mice from autoimmune diabetes by inducing CD4+ regulatory T-cells. Diabetes 48:2150-2156. [DOI] [PubMed] [Google Scholar]
  • 25.Quiding, M., I. Nordstrom, A. Kilander, G. Andersson, L. Å. Hanson, J. Holmgren, and C. Czerkinsky. 1991. Intestinal immune responses in humans. Oral cholera vaccination induces strong intestinal antibody responses and interferon-gamma production and evokes local immunological memory. J. Clin. Investig. 88:143-148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Quiding-Järbrink, M., G. Granström, I. Nordström, J. Holmgren, and C. Czerkinsky. 1995. Induction of compartmentalized B cell responses in the human tonsils. Infect. Immun. 63:853-857. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Quiding-Järbrink, M., I. Nordström, G. Granström, E. C. Butcher, A. I. Lazarovits, A. Kilander, M. Jertborn, J. Holmgren, and C. Czerkinsky. 1997. Differential expression of tissue-specific adhesion molecules on human circulating antibody-forming cells after systemic, enteric, and nasal immunization. A molecular basis for the compartmentalization of effector B cell responses. J. Clin. Investig. 99:1281-1286. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Quiding-Järbrink, M., I. Ahlstedt, C. Lindholm, E. L. Johansson, and H. Lönroth. 2001. Homing commitment of lymphocytes activated in the human gastric and intestinal mucosa. Gut 49:519-525. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Rose, J. R., M. B. Williams, L. S. Rott, E. C. Butcher, and H. B. Greenberg. 1998. Expression of the mucosal homing receptor α4β7 correlates with the ability of CD8+ memory T cells to clear rotavirus infection. J. Virol. 72:726-730. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Rott, L. S., J. R. Rose, D. Bass, M. B. Williams, H. B. Greenberg, and E. C. Butcher. 1997. Expression of mucosal homing receptor α4β7 by circulating CD4+ cells with memory for intestinal rotavirus. J. Clin. Investig. 100:1204-1208. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Sikorski, E. E., R. Hallmann, E. L. Berg, and E. C. Butcher. 1993. The Peyer's patch high endothelial receptor for lymphocytes, the mucosal vascular addressin, is induced on a murine endothelial cell line by tumor necrosis factor-alpha and IL-1. J. Immunol. 151:5239-5250. [PubMed] [Google Scholar]
  • 32.Springer, T. A. 1994. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 76:301-314. [DOI] [PubMed] [Google Scholar]
  • 33.Sun, J. B., B. L. Li, C. Czerkinsky, and J. Holmgren. 2000. Enhanced immunological tolerance against allograft rejection by oral administration of allogeneic antigen linked to cholera toxin B subunit. Clin. Immunol. 97:130-139. [DOI] [PubMed] [Google Scholar]
  • 34.Williams, M. B., J. R. Rose, L. S. Rott, M. A. Franco, H. B. Greenberg, and E. C. Butcher. 1998. The memory B cell subset responsible for the secretory IgA response and protective humoral immunity to rotavirus expresses the intestinal homing receptor α4β7. J. Immunol. 161:4227-4235. [PubMed] [Google Scholar]
  • 35.Wright, N., A. Hidalgo, J. M. Rodriguez-Frade, S. F. Soriano, M. Mellado, M. Parmo-Cabanas, M. J. Briskin, and J. Teixido. 2002. The chemokine stromal cell-derived factor-1 alpha modulates alpha 4 beta 7 integrin-mediated lymphocyte adhesion to mucosal addressin cell adhesion molecule-1 and fibronectin. J. Immunol. 168:5268-5277. [DOI] [PubMed] [Google Scholar]
  • 36.Wurbel, M. A., J. M. Philippe, C. Nguyen, G. Victorero, T. Freeman, P. Wooding, A. Miazek, M. G. Mattei, M. Malissen, B. R. Jordan, B. Malissen, A. Carrier, and P. Naquet. 2000. The chemokine TECK is expressed by thymic and intestinal epithelial cells and attracts double- and single-positive thymocytes expressing the TECK receptor CCR9. Eur. J. Immunol. 30:262-271. [DOI] [PubMed] [Google Scholar]
  • 37.Zabel, B. A., W. W. Agace, J. J. Campbell, H. M. Heath, D. Parent, A. I. Roberts, E. C. Ebert, N. Kassam, S. Qin, M. Zovko, G. J. LaRosa, L.-L. Yang, D. Soler, E. C. Butcher, P. D. Ponath, C. M. Parker, and D. P. Andrew. 1999. Human G protein-coupled receptor GPR-9-6/CC chemokine receptor 9 is selectively expressed on intestinal homing T lymphocytes, mucosa lymphocytes, and thymocytes and is required for thymus-expressed chemokine-mediated chemotaxis. J. Exp. Med. 190:1241-1255. [DOI] [PMC free article] [PubMed] [Google Scholar]

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