THEMES
Mucosal Immunity and Inflammation
II. The yin and yang of T cells in intestinal inflammation: pathogenic and protective roles in a mouse colitis model*

Hilde de Winter, Hilde Cheroutre, and Mitchell Kronenberg

Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121


    ABSTRACT
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ABSTRACT
INTRODUCTION
COLITIS CAN BE INDUCED...
HISTOPATHOLOGIC CHANGES...
PHENOTYPIC SIMILARITIES BETWEEN...
THE ROLE OF PROINFLAMMATORY...
HOW DO CD4+CD45RBLOW T...
THE ROLE OF BACTERIAL...
CONCLUSIONS
REFERENCES

Inflammatory bowel disease (IBD) is a multifactorial immune disorder of uncertain etiology. The advent of several mouse models of mucosal inflammation that resemble IBD has provided insight into the mechanisms governing both normal and pathological mucosal immune function. In a widely used adoptive transfer model, the injection into immunodeficient mice of a subset of CD4+ T lymphocytes, the CD4+CD45RBhigh cells, leads to inflammation of the intestine. Pathogenesis is due in part to the secretion of proinflammatory cytokines. The induction of colitis can be prevented by cotransfer of another CD4+ subpopulation, the CD4+CD45RBlow T cells. This population behaves analogously to the CD4+CD45RBhigh population in terms of the acquisition of activation markers and homing to the host intestine. However, their lymphokine profile when activated is different, and anti-inflammatory cytokines secreted and/or induced by CD4+CD45RBlow T cells prevent colitis. In this themes article, a description of the adoptive transfer model is given, the factors that promote and prevent colitis pathogenesis are discussed, and some controversial aspects of the model are addressed.

adoptive transfer; immunodeficient mice; inflammatory bowel disease; CD4+CD45RBhigh cells


    INTRODUCTION
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ABSTRACT
INTRODUCTION
COLITIS CAN BE INDUCED...
HISTOPATHOLOGIC CHANGES...
PHENOTYPIC SIMILARITIES BETWEEN...
THE ROLE OF PROINFLAMMATORY...
HOW DO CD4+CD45RBLOW T...
THE ROLE OF BACTERIAL...
CONCLUSIONS
REFERENCES

INFLAMMATORY BOWEL DISEASE (IBD) in humans, mainly encompassing Crohn's disease and ulcerative colitis, is a complex multifactorial immunological disorder. Studies of immunoreactive cells and proinflammatory mediators in the intestinal tissue of patients have suggested that IBD is the result of dysregulated immune responses to enteric antigens. Although there is now evidence that Crohn's disease is driven by the secretion of the so-called Th1 or proinflammatory cytokines, including interleukin (IL)-12, interferon-gamma (IFN-gamma ), and tumor necrosis factor (TNF), it has been proposed that ulcerative colitis is better classified as an IL-4- and IL-5- or a Th2-driven inflammation (26).


    COLITIS CAN BE INDUCED FOLLOWING TRANSFER OF SYNGENEIC T CELLS
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ABSTRACT
INTRODUCTION
COLITIS CAN BE INDUCED...
HISTOPATHOLOGIC CHANGES...
PHENOTYPIC SIMILARITIES BETWEEN...
THE ROLE OF PROINFLAMMATORY...
HOW DO CD4+CD45RBLOW T...
THE ROLE OF BACTERIAL...
CONCLUSIONS
REFERENCES

Several mouse models of experimentally induced or spontaneously occurring colitis are now available for examination of the pathogenesis of IBD. One of these, which involves the adoptive transfer of the CD4+CD45RBhigh T cell subpopulation to immunodeficient recipients, is the topic of this themes article. This rodent model is particularly attractive for study of the role of T cells in the induction of intestinal inflammation because it is reproducible, it is relatively easy to induce, it has a predictable time course, and it is highly subject to manipulation from a genetic and immunological viewpoint. Furthermore, it bears some resemblance to the clinical course, the therapeutic response, and the inflammatory mediator profile of some forms of IBD.

The transfer of spleen- or lymph node-derived syngeneic or coisogeneic CD4+CD45RBhigh T cells from wild-type donor mice into immunodeficient severe combined immunodeficient (SCID) or recombination activating gene (RAG)-/- recipients leads to wasting and intestinal inflammation (17), starting 3-5 wk after transfer. In contrast, in most cases, the transfer of total, unfractionated CD4+ T cells, or transfer of the CD4+CD45RBlow subset, does not induce wasting. Moreover, the CD4+CD45RBlow subset inhibits the potential of the CD4+CD45RBhigh population to induce disease (15) (see Fig. 1). Although most groups working with this transfer model obtained comparable results when transferring CD4+CD45RBhigh and CD4+CD45RBlow T cells, some controversy exists, as one group consistently reports the induction of colitis by transferring total, unfractionated CD4+ T cells, albeit later than when CD4+CD45RBhigh cells are transferred (19). Most likely the CD4+CD45RBhigh population is enriched for the pathogenic precursors, and environmental conditions can influence the number of these precursors present in the total donor population. It should be emphasized that the transfers in this model do not cross a major histocompatibility barrier leading to graft vs. host disease. Taken together, the data imply that normal mice have subsets of T lymphocytes that are capable of causing colitis and that these cells are kept in check by other T lymphocytes. After transfer into an immunodeficient recipient lacking the inhibitory T cell subsets, the pathogenic T cells cause disease due to their expansion and cytokine secretion.


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Fig. 1.   Donor and recipient (host) factors that promote disease are shown on the left; those that prevent disease are shown on the right. IFN-gamma , interferon-gamma ; IL, interleukin; NK cells, natural killer cells; TGF-beta , transforming growth factor-beta ; TNF, tumor necrosis factor; STAT4, signal transducer and activator of transcription-4.


    HISTOPATHOLOGIC CHANGES FOLLOWING T CELL TRANSFER
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ABSTRACT
INTRODUCTION
COLITIS CAN BE INDUCED...
HISTOPATHOLOGIC CHANGES...
PHENOTYPIC SIMILARITIES BETWEEN...
THE ROLE OF PROINFLAMMATORY...
HOW DO CD4+CD45RBLOW T...
THE ROLE OF BACTERIAL...
CONCLUSIONS
REFERENCES

Histopathological inflammation in diseased recipients extends diffusely from the cecum to the rectum. It is limited to the mucosa of mildly affected mice but is transmural in severely affected mice. Lesions consist of mucin depletion, epithelial hyperplasia, and increases in intraepithelial lymphocyte numbers. Less frequent findings include ulceration with fibrosis, crypt abscesses, crypt loss, and granulomatous inflammation. Furthermore, there is increased epithelial and lamina propria expression of major histocompatibility class II antigens (13). This increased expression is apparently due to IFN-gamma and TNF production by Th1 cells. In general, these lesions have some features in common with ulcerative colitis, including their diffuse distribution, restriction primarily to the large intestine, and mucin depletion. On the other hand, they also share features with Crohn's disease, including the transmural nature of the infiltration, the predominance of lymphocytes and macrophages, and the presence of rare crypt abscesses.

The injected T cells do not migrate exclusively to the intestine. Histological analysis of CD4+CD45RBhigh-transferred SCID mice revealed inflammatory lesions in the stomach (84%), liver (44%), and lungs (26%) (13). In one set of experiments, the reconstitution of SCID mice resulted in skin alterations that strikingly resemble human psoriasis both clinically and histopathologically and with regard to cytokine expression (20). Furthermore, in our own recent experiments, we obtained a substantial fraction of RAG -/- recipients whose primary site of inflammation is in the lungs (De Winter and Cheroutre, unpublished observations). The occurrence of inflammation in different sites in the immunodeficient recipients is likely to reflect environmental differences in animal colonies. For example, as in other animal models of colitis, bacterial flora are necessary for pathogenesis in this transfer model (2) and alterations in the flora in different vivaria could be critical for determining both the predominant site and severity of the resulting inflammation.


    PHENOTYPIC SIMILARITIES BETWEEN PATHOGENIC AND DISEASE-PREVENTING T CELL POPULATIONS
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ABSTRACT
INTRODUCTION
COLITIS CAN BE INDUCED...
HISTOPATHOLOGIC CHANGES...
PHENOTYPIC SIMILARITIES BETWEEN...
THE ROLE OF PROINFLAMMATORY...
HOW DO CD4+CD45RBLOW T...
THE ROLE OF BACTERIAL...
CONCLUSIONS
REFERENCES

What distinguishes the CD4+CD45RBhigh T cells from their CD4+CD45RBlow counterparts? At the phenotypic level, after transfer, surprisingly little distinction is present. Both donor populations can colonize the host intestine, although the CD4+CD45RBhigh T cells are slightly more efficient at doing this. Regardless of the donor population, the donor T cells in the intestine have an activated phenotype, including low levels of expression of CD45RB, even when the cells originally injected were CD45RBhigh, low levels of expression of the lymph node homing receptor CD62L, and high levels of expression of the activation marker CD69 (2). Many of the donor T cells found in the intestine also express a mucosal-specific integrin composed of alpha E- and beta 7-subunits. After adoptive transfer, both the large and small intestines are extensively colonized, although inflammation is seen predominantly in the large intestine.

The level of expression of CD45RB on CD4+ T cells is widely believed to distinguish naive (CD45RBhigh) from activated or memory (CD45RBlow) cells in normal mice. The suitability of CD45RBlow as a stable marker of activation or memory is questionable because T cells can both increase and decrease their level of CD45RB expression. The results from some studies have indicated that there may be two distinct types of CD4+ memory T cells: the CD45RBlow and CD45RBhigh "revertant" (3). The CD4+CD45RBhigh memory cells produce high levels of proinflammatory Th1 cytokines, such as IL-2, IFN-gamma , and TNF, but little IL-4 in response to a variety of mitogenic stimuli, whereas the CD45RBlow population tends to produce Th2-type cytokines, such as IL-4 (14). This is consistent with the difference between the two T cell subpopulations in the pathogenesis of colitis.


    THE ROLE OF PROINFLAMMATORY CYTOKINES IN COLITIS PATHOGENESIS
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ABSTRACT
INTRODUCTION
COLITIS CAN BE INDUCED...
HISTOPATHOLOGIC CHANGES...
PHENOTYPIC SIMILARITIES BETWEEN...
THE ROLE OF PROINFLAMMATORY...
HOW DO CD4+CD45RBLOW T...
THE ROLE OF BACTERIAL...
CONCLUSIONS
REFERENCES

To dissect the mechanisms of colitis induction, it is important to establish which cytokines are involved in the pathogenic pathway. There is broad consensus that the colitis induced by the CD4+CD45RBhigh population is due to a proinflammatory, Th1-type immune response by the transferred CD4+ T cells. In this regard, the CD4+CD45RBhigh adoptive transfer model resembles several other models for intestinal inflammation, including the colitis induced by administration of trinitrobenzene sulfonic acid, the disease induced by bone marrow reconstitution of T cell- and natural killer (NK) cell-deficient Tgepsilon 26 transgenic mice, the colitis in mice deficient for the trimeric G protein Galpha i-2, and the spontaneous colitis that occurs in IL-10-deficient mice (22). Whereas the results from clinical trials suggest that TNF is critically important for the pathogenesis of Crohn's disease in some patients (24), in the adoptive transfer model the respective contributions to intestinal inflammation of the key players in a typical Th1 response (such as IFN-gamma , TNF, and others) remain to be determined. IL-12, produced by activated macrophages and dendritic cells, is the principal Th1-inducing cytokine. Many microbial products stimulate IL-12 production. IL-12 in turn activates three transcription factors: signal transducer and activator of transcription (STAT)-1, STAT3, and STAT4. Of these, STAT4 seems to be exclusively activated by IL-12 and no other cytokine. Consistent with the importance of an IL-12- and STAT4-mediated pathway for Th1 cytokine induction, it has been found that mice deficient for either the IL-12 or STAT4 genes have markedly reduced Th1 responses (1). It is surprising, therefore, that reconstitution of immunodeficient mice with CD4+CD45RBhigh T cells in the presence of anti-IL-12 monoclonal antibody (MAb), or with T cells from STAT4-deficient mice, does not abrogate the disease completely. The disease that results is much milder, however, with lower frequencies of IFN-gamma producing T cells in the mesenteric lymph nodes and colonic lamina propria (21). These studies suggest that factors outside the IL-12/STAT4 pathway contribute to the development of the more chronic forms of intestinal inflammation. IL-18, the IFN-gamma -inducing factor, is a potential candidate because this cytokine has been shown to have a significant effect on the long-term ability of T cells to produce IFN-gamma and because it has its highest expression in the intestinal epithelial cells (11, 23). Furthermore, it has been shown to synergize with IL-2 in Th1 cytokine induction.

Although the results from a number of experiments indicate that IFN-gamma is important for the induction of colitis in animal model systems, it is not clear if it acts directly, by causing damage to colonic epithelial cells, or if it acts primarily to activate macrophages with the subsequent production of inflammatory mediators such as reactive oxygen and nitrogen intermediates (IL-1, IL-6, IL-12, and TNF), some of which have been shown to cause intestinal damage. Moreover, IFN-gamma may influence cell trafficking by regulating adhesion molecule expression. The potential importance of this cytokine in contributing to pathogenesis is suggested by the finding that neutralization of IFN-gamma using MAbs significantly attenuates colitis development in mice reconstituted with CD4+CD45RBhigh T cells. Unfortunately, the results obtained from transfers of T cells from IFN-gamma -deficient donors do not bring more clarity. One group reported that the adoptive transfer of CD4+CD45RBhigh cells from IFN-gamma knockout mice does not induce colitis (10). Surprisingly, this is in flagrant contradiction to the findings of another group, who reported that when CD4+CD45RBhigh T cells from IFN-gamma knockout donors are transferred large numbers of reconstituted recipients develop wasting and colitis, often of comparable severity to that seen in animals reconstituted with wild-type cells (21). It is therefore likely that Th1 cells can mediate intestinal inflammation via several mechanisms, not all of which result from the production of IFN-gamma and which are mostly but not entirely governed by the ability to produce and respond to IL-12 (see Fig. 1). Ultimately, this is most likely achieved by the concerted expression of several cytokines and cytotoxic molecules. In colitic mice, T cells express TNF at a similar frequency, regardless of whether or not IFN-gamma is expressed by the same cells, and treatment with anti-TNF MAb also can ameliorate disease, although it is not as effective as IFN-gamma MAb treatment (15).


    HOW DO CD4+CD45RBLOW T CELLS PREVENT DISEASE?
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ABSTRACT
INTRODUCTION
COLITIS CAN BE INDUCED...
HISTOPATHOLOGIC CHANGES...
PHENOTYPIC SIMILARITIES BETWEEN...
THE ROLE OF PROINFLAMMATORY...
HOW DO CD4+CD45RBLOW T...
THE ROLE OF BACTERIAL...
CONCLUSIONS
REFERENCES

Downregulation of pathogenesis by CD4+CD45RBlow T cells may be due to the production or induction of a cytokine repertoire that antagonizes either the expansion, localization, differentiation, or effector function of the T cells involved in the inflammatory response. Because of the well-documented anti-inflammatory properties of IL-10 and the spontaneous colitis that develops in IL-10-deficient mice (12), it would seem likely that IL-10 would play an important role in the inhibition of colitis mediated by CD4+CD45RBlow T cells. Consistent with this hypothesis, the systemic administration of recombinant IL-10 significantly inhibits the development of colitis due to T cell transfer (18). Likewise, cotransfer of T cells from transgenic mice that produce IL-10 under the control of the IL-2 promoter also prevents the induction of colitis by the CD4+CD45RBhigh population (9). Furthermore, regulatory T cells called Tr1 cells, which primarily secrete IL-10 as a result of prolonged culture in high levels of IL-10, also can prevent disease on cotransfer with CD4+CD45RBhigh T cells (8). It is therefore surprising that the protection from colitis mediated by the CD4+CD45RBlow population was not diminished by neutralization of IL-10 with specific MAbs, although it remains possible in this case that the neutralization of IL-10 was not complete (16). In the same experiment, however, the neutralization of transforming growth factor-beta (TGF-beta ) with specific MAbs did abrogate the disease-preventing effect of the CD4+CD45RBlow population. Several questions remain unresolved concerning the mechanism whereby the CD4+CD45RBlow T cells exert their anti-inflammatory effects. First, it remains uncertain if TGF-beta and IL-10 act in a single pathway, perhaps by the TGF-beta -mediated induction of IL-10 synthesis, or if they prevent inflammation through independent pathways. Furthermore, it is not known whether the anti-inflammatory cytokines are produced primarily by the CD4+CD45RBlow T cells themselves or if they are induced in other cell types. The results from the IL-10 transgenic mice and the transfer of Tr1 cells, however, suggest that T cell-derived IL-10 is of critical importance. Third, it is not known if the CD4+CD45RBlow T cells prevent disease by acting locally in the intestine or elsewhere. Finally, additional mechanisms for the prevention of disease pathogenesis must be considered. For example, host NK cells have recently been demonstrated to inhibit colitis induction by transfer of CD4+CD45RBhigh T cells, apparently in a perforin-dependent way (7).


    THE ROLE OF BACTERIAL PRODUCTS IN THE INDUCTION OF COLITIS
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ABSTRACT
INTRODUCTION
COLITIS CAN BE INDUCED...
HISTOPATHOLOGIC CHANGES...
PHENOTYPIC SIMILARITIES BETWEEN...
THE ROLE OF PROINFLAMMATORY...
HOW DO CD4+CD45RBLOW T...
THE ROLE OF BACTERIAL...
CONCLUSIONS
REFERENCES

The antigen specificity and the original site of encounter with antigen by the transferred CD4+CD45RBhigh population remain unknown. Published evidence suggests that T cell expansion is occurring in the lamina propria and the epithelial layer of the small and large intestine (19). T cell homing to the intestine is however believed to require previous antigen contact; therefore, it is likely that the initial priming with antigen occurred in the spleen or some other site. The published data also suggest that the donor-derived T lymphocytes are polyclonally activated, as reflected by a diverse T cell repertoire. This suggests the presence of a polyclonal mitogen or a polyclonal response against different gut-derived antigens (19).

Any infectious agent or luminal toxin that is capable of breaking the mucosal barrier may be able to create an inflammatory response that can become chronic in the genetically susceptible host. The normal tolerance (or ignorance) that exists toward the indigenous intestinal flora is broken in experimental colitis (6). The finding that significant bowel pathology is limited to the large intestine supports the hypothesis that bacteria play a crucial role in pathogenesis, as the colon contains the bulk of the flora. Consistent with this, germ-free housing of the SCID recipients significantly attenuates the extent of disease and colitis can be ameliorated by antibiotic treatment of the SCID recipients (2).

The dramatic skewing toward a Th1 response in the SCID recipients could reflect IL-12 secretion and polyclonal activation of T cells, possibly induced by superantigens, mitogens, or other cell wall products derived from luminal bacteria of the colon. In particular, Helicobacter hepaticus has been shown to cause colitis in immunodeficient mice but causes no intestinal pathology in immunocompetent animals (25). Furthermore, when CD4+CD45RBhigh T cells are injected into Helicobacter-infected animals, the resulting intestinal inflammation is more severe than the one resulting from T cell transfer or Helicobacter infection alone (5).

Finally, the question remains as to why do the SCID mice become ill following CD4+CD45RBhigh T cell transfer. The clear implication from the CD4+CD45RBlow cotransfer studies is that the SCID recipient lacks an important regulatory or anti-inflammatory T cell population. It remains possible, however, that the SCID mouse has additional defects as a result of its total immunodeficiency. For example, gamma delta -intraepithelial lymphocytes might function to maintain the epithelial barrier through the synthesis of keratinocyte growth factor and other cytokines (4), and the absence of this lymphocyte population in immunodeficient recipients could contribute to disease susceptibility by causing impaired barrier function or an impaired healing response to local inflammation.


    CONCLUSIONS
TOP
ABSTRACT
INTRODUCTION
COLITIS CAN BE INDUCED...
HISTOPATHOLOGIC CHANGES...
PHENOTYPIC SIMILARITIES BETWEEN...
THE ROLE OF PROINFLAMMATORY...
HOW DO CD4+CD45RBLOW T...
THE ROLE OF BACTERIAL...
CONCLUSIONS
REFERENCES

In summary, the adoptive transfer of CD4+CD45RBhigh T cells to immunodeficient recipients provides an attractive and highly versatile model for the study of the etiopathogenesis of mouse intestinal inflammation and of the factors that prevent inflammation. With the use of genetically altered donors or recipients, such as animals deficient in cytokine genes, and with the use of treatments with neutralizing antibodies or with recombinant cytokines, the exact role of particular mediators in pathogenesis can in principle be unraveled. Such an analysis should aid in understanding both the etiopathogenesis and the treatment of human IBD, in particular Crohn's disease, which is mediated in part by an analogous proinflammatory cytokine cascade.


    ACKNOWLEDGEMENTS

The title of this article was inspired by a review from J. P. Allison and M. F. Krummel (The yin and yang of T cell costimulation, Science 270: 932-933, 1995).


    FOOTNOTES

* Second in a series of invited articles on Mucosal Immunity and Inflammation.

This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-46763 (M. Kronenberg) and DK-54451 (H. Cheroutre). This is publication number 292 from the La Jolla Institute for Allergy and Immunology.

Address for reprint requests and other correspondence: M. Kronenberg, Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121 (E-mail: mitch{at}liai.org).


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
COLITIS CAN BE INDUCED...
HISTOPATHOLOGIC CHANGES...
PHENOTYPIC SIMILARITIES BETWEEN...
THE ROLE OF PROINFLAMMATORY...
HOW DO CD4+CD45RBLOW T...
THE ROLE OF BACTERIAL...
CONCLUSIONS
REFERENCES

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9.   Hagenbaugh, A., S. Sharma, S. M. Dubinett, S. H. Y. Wei, R. Aranda, H. Cheroutre, D. J. Fowell, S. Binder, B. Tsao, R. M. Locksley, K. W. Moore, and M. Kronenberg. Altered immune responses in interleukin 10 transgenic mice. J. Exp. Med. 185: 2101-2110, 1997[Abstract/Free Full Text].

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17.   Powrie, F., M. W. Leach, S. Mauze, L. B. Caddle, and R. L. Coffman. Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C.B-17 scid mice. Int. Immunol. 5: 1461-1471, 1993[Abstract].

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22.   Stallmach, A., W. Strober, T. T. MacDonald, H. Lochs, and M. Zeitz. Induction and modulation of gastrointestinal inflammation. Immunol. Today 19: 438-441, 1998[Medline].

23.   Takeuchi, M., Y. Nishizaki, O. Sano, T. Ohta, M. Ikeda, and M. Kurimoto. Immunohistochemical and immuno-electron-microscopic detection of interferon-gamma -inducing factor ("interleukin-18") in mouse intestinal epithelial cells. Cell Tissue Res. 289: 499-503, 1997[Medline].

24.   Targan, S. R., S. B. Hanauer, S. J. van Deventer, L. Mayer, D. H. Present, T. Braakman, K. L. DeWoody, T. F. Schaible, and P. J. Rutgeerts. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha  for Crohn's disease. Crohn's disease cA2 study group. N. Engl. J. Med. 337: 1029-1035, 1997[Abstract/Free Full Text].

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Am J Physiol Gastroint Liver Physiol 276(6):G1317-G1321
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