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Mizoguchi E, Low D, Ezaki Y, Okada T. Recent updates on the basic mechanisms and pathogenesis of inflammatory bowel diseases in experimental animal models. Intest Res 2020; 18:151-167. [PMID: 32326669 PMCID: PMC7206339 DOI: 10.5217/ir.2019.09154] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 02/10/2020] [Indexed: 12/19/2022] Open
Abstract
The specific pathogenesis underlining inflammatory bowel disease (IBD) is very complicated, and it is further more difficult to clearly explain the pathophysiology of 2 major forms of IBD, Crohn’s disease (CD) and ulcerative colitis (UC), and both disorders affect individuals throughout life. Despite every extensive effort, the interplay among genetic factors, immunological factors, environmental factors and intestinal microbes is still completely unrevealed. Animal models are indispensable to find out mechanistic details that will facilitate better preclinical setting to target specific components involved in the pathogenesis of IBD. Based on many recent reports, dysbiosis of the commensal microbiota is implicated in the pathogenesis of several diseases, not only IBD but also colon cancer, obesity, psoriasis as well as allergic disorders, in both human and animal models. Advanced technologies including cell-specific and inducible knockout systems, which are recently employed to mouse IBD models, have further enhanced the ability of developing new therapeutic strategies for IBD. Furthermore, data from these mouse models highlight the critical involvement of dysregulated immune responses and impaired colonic epithelial defense system in the pathogenesis of IBD. In this review, we will explain from the history of animal models of IBD to the recent reports of the latest compounds, therapeutic strategies, and approaches tested on IBD animal models.
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Affiliation(s)
- Emiko Mizoguchi
- Department of Immunology, Kurume University School of Medicine, Kurume, Japan.,Department of Molecular Microbiology and Immunology, Brown University Warren Alpert Medical School, Providence, RI, USA
| | - Daren Low
- Crohn's & Colitis Society of Singapore, Singapore
| | - Yui Ezaki
- Department of Immunology, Kurume University School of Medicine, Kurume, Japan
| | - Toshiyuki Okada
- Department of Immunology, Kurume University School of Medicine, Kurume, Japan
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Mizoguchi A, Takeuchi T, Himuro H, Okada T, Mizoguchi E. Genetically engineered mouse models for studying inflammatory bowel disease. J Pathol 2015; 238:205-19. [PMID: 26387641 DOI: 10.1002/path.4640] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Revised: 09/05/2015] [Accepted: 09/14/2015] [Indexed: 12/11/2022]
Abstract
Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition that is mediated by very complex mechanisms controlled by genetic, immune, and environmental factors. More than 74 kinds of genetically engineered mouse strains have been established since 1993 for studying IBD. Although mouse models cannot fully reflect human IBD, they have provided significant contributions for not only understanding the mechanism, but also developing new therapeutic means for IBD. Indeed, 20 kinds of genetically engineered mouse models carry the susceptibility genes identified in human IBD, and the functions of some other IBD susceptibility genes have also been dissected out using mouse models. Cutting-edge technologies such as cell-specific and inducible knockout systems, which were recently employed to mouse IBD models, have further enhanced the ability of investigators to provide important and unexpected rationales for developing new therapeutic strategies for IBD. In this review article, we briefly introduce 74 kinds of genetically engineered mouse models that spontaneously develop intestinal inflammation.
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Affiliation(s)
- Atsushi Mizoguchi
- Department of Immunology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Takahito Takeuchi
- Department of Immunology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Hidetomo Himuro
- Department of Immunology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Toshiyuki Okada
- Department of Immunology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Emiko Mizoguchi
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Fruit Street, Boston, MA, 02114, USA
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Laydon DJ, Bangham CRM, Asquith B. Estimating T-cell repertoire diversity: limitations of classical estimators and a new approach. Philos Trans R Soc Lond B Biol Sci 2015; 370:20140291. [PMID: 26150657 PMCID: PMC4528489 DOI: 10.1098/rstb.2014.0291] [Citation(s) in RCA: 125] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/03/2015] [Indexed: 12/26/2022] Open
Abstract
A highly diverse T-cell receptor (TCR) repertoire is a fundamental property of an effective immune system, and is associated with efficient control of viral infections and other pathogens. However, direct measurement of total TCR diversity is impossible. The diversity is high and the frequency distribution of individual TCRs is heavily skewed; the diversity therefore cannot be captured in a blood sample. Consequently, estimators of the total number of TCR clonotypes that are present in the individual, in addition to those observed, are essential. This is analogous to the 'unseen species problem' in ecology. We review the diversity (species richness) estimators that have been applied to T-cell repertoires and the methods used to validate these estimators. We show that existing approaches have significant shortcomings, and frequently underestimate true TCR diversity. We highlight our recently developed estimator, DivE, which can accurately estimate diversity across a range of immunological and biological systems.
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MESH Headings
- Animals
- Gene Rearrangement, T-Lymphocyte
- Genetic Variation
- Host-Pathogen Interactions/genetics
- Host-Pathogen Interactions/immunology
- Humans
- Lymphocyte Count
- Models, Genetic
- Models, Immunological
- Receptors, Antigen, T-Cell/chemistry
- Receptors, Antigen, T-Cell/genetics
- Receptors, Antigen, T-Cell/immunology
- Statistics, Nonparametric
- T-Lymphocytes/immunology
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Affiliation(s)
- Daniel J Laydon
- Section of Immunology, Wright-Fleming Institute, Imperial College School of Medicine, London W2 1PG, UK
| | - Charles R M Bangham
- Section of Immunology, Wright-Fleming Institute, Imperial College School of Medicine, London W2 1PG, UK
| | - Becca Asquith
- Section of Immunology, Wright-Fleming Institute, Imperial College School of Medicine, London W2 1PG, UK
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Boirivant M. Experimental Models of Gastrointestinal Inflammatory Diseases. Mucosal Immunol 2015. [DOI: 10.1016/b978-0-12-415847-4.00079-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Mizoguchi A. Animal models of inflammatory bowel disease. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2012; 105:263-320. [PMID: 22137435 DOI: 10.1016/b978-0-12-394596-9.00009-3] [Citation(s) in RCA: 182] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition that is medicated by genetic, immune, and environmental factors. At least 66 different kinds of animal models have been established to study IBD, which are classified primarily into chemically induced, cell-transfer, congenial mutant, and genetically engineered models. These IBD models have provided significant contributions to not only dissect the mechanism but also develop novel therapeutic strategies for IBD. In addition, recent advances on genetically engineered techniques such as cell-specific and inducible knockout as well as knockin mouse systems have brought novel concepts on IBD pathogenesis to the fore. Further, mouse models, which lack some IBD susceptibility genes, have suggested more complicated mechanism of IBD than previously predicted. This chapter summarizes the distinct feature of each murine IBD model and discusses the previous and current lessons from the IBD models.
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Affiliation(s)
- Atsushi Mizoguchi
- Department of Pathology, Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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7
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Saleh M, Elson CO. Experimental inflammatory bowel disease: insights into the host-microbiota dialog. Immunity 2011; 34:293-302. [PMID: 21435584 DOI: 10.1016/j.immuni.2011.03.008] [Citation(s) in RCA: 118] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2011] [Indexed: 12/14/2022]
Abstract
Inflammatory bowel disease appears to result from an abnormal host immune response to the intestinal microbiota. Experimental models have allowed the dissection of the complex dialog between the host and its microbiota. Through genetic manipulation of the host genome the immune compartments, cells, molecules, and genes that are critical for maintenance of intestinal homeostasis are being identified. Genetic association studies in humans have identified over 100 susceptibility loci. Although there is remarkable coherence between the experimental model and the human genetic data, a full understanding of the mechanisms involved in genetic susceptibility to IBD and of gene-gene and gene-environmental interactions will require a "next generation" of experimental models.
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Affiliation(s)
- Maya Saleh
- Department of Medicine, McGill University, Montreal, Quebec, Canada H3G 0B1.
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Immunomodulatory and therapeutic potential of a mycelial lectin from Aspergillus nidulans. Appl Biochem Biotechnol 2011; 165:624-38. [PMID: 21590306 DOI: 10.1007/s12010-011-9281-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2010] [Accepted: 05/04/2011] [Indexed: 10/18/2022]
Abstract
Lectins bind to surface receptors on target cells, and activate a cascade of events, eventually leading to altered immune status of host. The immunomodulatory potential of purified lectin from Aspergillus nidulans was evaluated in Swiss albino mice treated intraperitoneally with seven different doses of purified lectin. Lectin prevented BSA-induced Arthus reaction and systemic anaphylaxis. The enhanced functional ability of macrophages was evident from respiratory burst activity and nitric oxide production in splenocyte cultures. Interferon-gamma and interleukin-6 levels were significantly up-regulated in treated groups. Maximum stimulatory effect was observed at the dose of 1.5 mg/kg body weight. Therapeutic potential of A. nidulans lectin was assessed against trinitrobenzene sulfonic acid-induced ulcerative colitis in male Wistar rats. Rats pre-treated with 80 mg/kg body weight of purified lectin intraperitoneally prior to colitis induction showed lesser disease severity and recovery within 7 days, while rats post-treated with the same dose showed recovery in 11 days. The results demonstrate immunomodulatory effects of A. nidulans lectin in Swiss albino mice, resulting in improved immune status of the animals and unfold its curative effect against ulcerative colitis in rat model. This is the first report on immunomodulatory and therapeutic potential of a lectin from microfungi.
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Tammariello AE, Milner JA. Mouse models for unraveling the importance of diet in colon cancer prevention. J Nutr Biochem 2010; 21:77-88. [PMID: 20122631 DOI: 10.1016/j.jnutbio.2009.09.014] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2009] [Revised: 07/30/2009] [Accepted: 09/21/2009] [Indexed: 01/28/2023]
Abstract
Diet and genetics are both considered important risk determinants for colorectal cancer, a leading cause of death worldwide. Several genetically engineered mouse models have been created, including the ApcMin mouse, to aid in the identification of key cancer related processes and to assist with the characterization of environmental factors, including the diet, which influence risk. Current research using these models provides evidence that several bioactive food components can inhibit genetically predisposed colorectal cancer, while others increase risk. Specifically, calorie restriction or increased exposure to n-3 fatty acids, sulforaphane, chafuroside, curcumin and dibenzoylmethane were reported protective. Total fat, calories and all-trans retinoic acid are associated with an increased risk. Unraveling the importance of specific dietary components in these models is complicated by the basal diet used, the quantity of test components provided and interactions among food components. Newer models are increasingly available to evaluate fundamental cellular processes, including DNA mismatch repair, immune function and inflammation as markers for colon cancer risk. Unfortunately, these models have been used infrequently to examine the influence of specific dietary components. The enhanced use of these models can shed mechanistic insights about the involvement of specific bioactive food and components and energy as determinants of colon cancer risk. However, the use of available mouse models to exactly represent processes important to human gastrointestinal cancers will remain a continued scientific challenge.
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Strober W, Fuss IJ. Experimental models of mucosal inflammation. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2009; 579:55-97. [PMID: 16620012 DOI: 10.1007/0-387-33778-4_5] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Warren Strober
- Mucosal Immunity Section, Laboratory of Host Defense NIAID, National Institutes of Health, Bethesda, MD, USA
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Mizoguchi A, Mizoguchi E. Inflammatory bowel disease, past, present and future: lessons from animal models. J Gastroenterol 2008; 43:1-17. [PMID: 18297430 DOI: 10.1007/s00535-007-2111-3] [Citation(s) in RCA: 126] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2007] [Accepted: 08/29/2007] [Indexed: 02/04/2023]
Abstract
Accumulating data from animal models indicate that Inflammatory bowel disease (IBD) is mediated by a much more complicated mechanism than previously predicted. For example, the role of an individual molecule in the pathogenesis of IBD distinctly differs depending on several factors, including the fundamental mechanism of induction of the disease, the target cell type, the phase of disease, and the environment. Therefore, it has been difficult in the past to fully explain the complicated mechanism. Novel concepts have recently been proposed to further explain the complicated mechanism of IBD. In this review, we introduce past, current, and possible future concepts for IBD models regarding T helper (Th) 1, Th2, and Th17, antigen sampling and presentation, regulatory cell networks, NOD2, Toll-like receptors, bacteria/epithelia interaction, stem cells, autophagy, microRNAs, and glycoimmunology, and we also discuss the relevance of these new concepts, developed at the bench (in animal models), to the bedside.
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Affiliation(s)
- Atsushi Mizoguchi
- Department of Pathology, Experimental Pathology, Simches 8234, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA
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Human gut microbiota and bifidobacteria: from composition to functionality. Antonie van Leeuwenhoek 2008; 94:35-50. [PMID: 18338233 DOI: 10.1007/s10482-008-9232-4] [Citation(s) in RCA: 157] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2007] [Accepted: 02/26/2008] [Indexed: 01/01/2023]
Abstract
The human gut is the home of an estimated 10(18) bacterial cells, many of which are uncharacterized or unculturable. Novel culture-independent approaches have revealed that the majority of the human gut microbiota consists of members of the phyla Bacteroidetes and Firmicutes. Nevertheless the role of bifidobacteria in gut ecology illustrates the importance of Actinomycetes and other Actinobacteria that may be underestimated. The human gut microbiota represents an extremely complex microbial community the collective genome of which, the microbiome, encodes functions that are believed to have a significant impact on human physiology. The microbiome is assumed to significantly enhance the metabolism of amino and glycan acids, the turnover of xenobiotics, methanogenesis and the biosynthesis of vitamins. Co-colonisation of the gut commensals Bifidobacterium longum and Bacteroides thetaiotaomicron in a murine model system revealed that the presence of bifidobacteria induced an expansion in the diversity of polysaccharides targeted for degradation by Bacteroides and also induced host genes involved in innate immunity. In addition, comparative analysis of individual human gut microbiomes has revealed various strategies that the microbiota use to adapt to the intestinal environment while also pointing to the existence of a distinct infant and adult-type microbiota.
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Mizoguchi E, Hachiya Y, Kawada M, Nagatani K, Ogawa A, Sugimoto K, Mizoguchi A, Podolsky DK. TNF receptor type I-dependent activation of innate responses to reduce intestinal damage-associated mortality. Gastroenterology 2008; 134:470-80. [PMID: 18242213 DOI: 10.1053/j.gastro.2007.11.055] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2006] [Accepted: 11/08/2007] [Indexed: 12/30/2022]
Abstract
BACKGROUND & AIMS Ligation of tumor necrosis factor (TNF) receptors (TNFRs) with TNF plays a critical role in the pathogenesis of human inflammatory bowel disease (IBD). However, it remains unclear which cell types activated through TNFR-associated signaling cascades are involved in the pathogenesis of colitis. METHODS Recombination activating gene-1 (RAG) knockout (KO) (no T or B cells)-based TNFR double and triple KO mice were generated. Bone marrow (BM) chimera mice in which BM-derived myeloid cells, but not colonic epithelial cells (CECs), express TNFRs were also generated. Colitis was induced by administration of dextran sodium sulfate (DSS) in distilled water. Murine lines and chimeras were assessed for disease severity, histopathology, apoptotic cell rate, epithelial proliferation, and bacterial invasion rate. RESULTS Following DSS administration, mice lacking both RAG and TNFR1 exhibited a high mortality (>80%) rate with an impaired CEC regeneration compared with RAG KO and RAG x TNFR2 double KO (DKO) mice. Transplantation of RAG KO-derived BM cells restored CEC regeneration and rescued the majority of recipient RAG x TNFR1 DKO mice from DSS-induced mortality. After BM transplantation, RAG x TNFR1 DKO mice exhibited an increased rate of apoptosis in the colonic lamina propria macrophages in association with the activation of caspases. In addition, BM reconstitution directly or indirectly enhanced the proliferation of CECs by activating mitogen-activated protein kinase and phosphoinositide-3 kinase/Akt pathways. CONCLUSIONS TNFR1-signaling cascade in colonic myeloid lineage cells contributes to the suppression of acute damage-associated mortality presumably by controlling CEC homeostasis.
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Affiliation(s)
- Emiko Mizoguchi
- Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
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Kawada M, Hachiya Y, Arihiro A, Mizoguchi E. Role of mammalian chitinases in inflammatory conditions. Keio J Med 2007; 56:21-7. [PMID: 17392594 DOI: 10.2302/kjm.56.21] [Citation(s) in RCA: 112] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
It has been hypothesized that dysregulated host/microbial interactions play a pivotal role in the pathogenesis of inflammatory bowel disease. However, the exact mechanisms underlying the induction and perpetuation of the intestinal disorder are unclear. Recently, we unexpectedly discovered significantly upregulated gene expression of chitinase 3-like-1 in inflamed colon of the dextran sulfate sodium-induced colitis model by employing the DNA-microarray analysis. Chitinase 3-like-1 has a chitin binding ability, but lacks the enzymatic activity of lysing microbial cell wall. Chitinase 3-like-1 protein is mainly expressed in colonic epithelial cells and macrophages in the inflamed colon of dextran sulfate sodium-induced colitis. Chitinase 3-like-1, which can be upregulated after pro-inflammatory cytokine stimulation, possesses an ability to enhance the adhesion and internalization of intracellular bacteria into colonic epithelial cells. Most importantly, in vivo neutralization of chitinase 3-like-1 significantly suppressed the development of dextran sulfate sodium-induced colitis by dramatically decreasing the bacterial adhesion and invasion into colonic epithelial cells. Furthermore, anti-chitinase 3-like-1 antibody-treated mice exhibited a significantly lower load of Salmonella typhimurium in peripheral organs as compared to control rabbit IgG-treated mice. Recently, it has been reported that acidic mammalian chitinase is expressed in the setting of T helper-2-associated inflammation and subsequently induces airway hyperresponsiveness in allergic asthma patients. In addition, pan-chitinase inhibitor significantly ameliorates T helper-2-mediated inflammation and airway hypersensitivity. These studies provide to be a novel insight into the physiological role of mammalian chitinases in host/microbial interactions, and inhibition of chitinase activity would be considered a novel therapeutic strategy of allergic and inflammatory disorders.
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Affiliation(s)
- Mayumi Kawada
- Gatrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
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Elson CO, Cong Y, Weaver CT. Alterations of T lymphocytes in inflammatory bowel diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2006; 579:133-48. [PMID: 16620016 DOI: 10.1007/0-387-33778-4_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Affiliation(s)
- Charles O Elson
- Division of Gastroenterology and Hepatology, University of Alabama, Birmingham, Alabama, USA
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Ley RE, Peterson DA, Gordon JI. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 2006; 124:837-48. [PMID: 16497592 DOI: 10.1016/j.cell.2006.02.017] [Citation(s) in RCA: 2261] [Impact Index Per Article: 119.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The human gut is populated with as many as 100 trillion cells, whose collective genome, the microbiome, is a reflection of evolutionary selection pressures acting at the level of the host and at the level of the microbial cell. The ecological rules that govern the shape of microbial diversity in the gut apply to mutualists and pathogens alike.
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Affiliation(s)
- Ruth E Ley
- Center for Genome Sciences, Washington University School of Medicine, St. Louis, MO 63108, USA
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Matsushita M, Takakuwa H, Matsubayashi Y, Nishio A, Ikehara S, Okazaki K. Appendix is a priming site in the development of ulcerative colitis. World J Gastroenterol 2005; 11:4869-74. [PMID: 16097061 PMCID: PMC4398739 DOI: 10.3748/wjg.v11.i31.4869] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: The role of the appendix has been highlighted in the pathogenesis of ulcerative colitis (UC). The aims of this study were to elucidate the immuno-imbalances in the appendix of UC patients, and to clarify the role of the appendix in the development of UC.
METHODS: Colonoscopic biopsy specimens of the appendix, transverse colon, and rectum were obtained from 86 patients with UC: active pancolitis (A-Pan; n = 15), active left-sided colitis (A-Lt; n = 25), A-Lt with appendiceal involvement (A-Lt/Ap; n = 10), inactive pancolitis (I-Pan; n = 14), and inactive left-sided colitis (I-Lt; n = 22), and from controls. In the isolated mucosal T cells, the CD4/CD8 ratio and proportion of activated CD4+ T cells were investigated, and compared with controls.
RESULTS: In the appendix, the CD4/CD8 ratio significantly increased in A-Lt and A-Lt/Ap. The ratio in the appendix also tended to increase in A-Pan. In the rectum, the ratio significantly increased in all UC groups. In the appendix, the proportion of CD4+CD69+ (early activation antigen) T cells significantly increased in all UC groups. In the rectum, the proportion of CD4+CD69+ T cells significantly increased only in A-Pan. The proportion of CD4+HLA-DR+ (mature activation antigen) T cells significantly increased only in the rectum of A-Pan, but not in the other areas of any groups.
CONCLUSION: The increased CD4/CD8 ratio and predominant infiltration of CD4+CD69+ T cells in the appendix suggest that the appendix is a priming site in the development of UC.
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Affiliation(s)
- Mitsunobu Matsushita
- Third Department of Internal Medicine, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi, Osaka 570-8506, Japan.
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Ohman L, Aström RG, Hultgren Hörnquist E. Impaired B cell responses to orally administered antigens in lamina propria but not Peyer's patches of Galphai2-deficient mice prior to colitis. Immunology 2005; 115:271-8. [PMID: 15885134 PMCID: PMC1782142 DOI: 10.1111/j.1365-2567.2005.02149.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Despite numerous studies on the intestinal immune system in patients with inflammatory bowel disease (IBD) and animal models of IBD, very little is known about the immune reactivity of mucosal lymphocytes following oral immunizations under these circumstances. The reactivity of Peyer's patch (PP) and lamina propria (LP) T and B lymphocytes in inhibitory G-protein alpha2 subunit-deficient (Galphai2-/-) mice developing an IBD resembling ulcerative colitis was investigated following repeated oral immunizations with keyhole limpet haemocyanin (KLH), together with the adjuvant cholera toxin, prior to colitis. The antigen-specific B-cell response in the LP of both the small and the large intestines was significantly reduced in Galphai2-/- as compared to wild-type mice. In contrast, the frequency of KLH-specific immunoglobulin (Ig)-producing cells in the PP did not differ between Galphai2-/- and wild-type mice, whereas the total frequency of Ig-producing cells as well as the frequency of enteric flora-specific Ig-producing cells in the PP was significantly increased in Galphai2-/- as compared to wild-type mice. Analysis of T cell responses following restimulation ex vivo with KLH revealed a dramatic increase in the production of interferon-gamma in mesenteric lymph node, PP and LP lymphocytes from Galphai2-deficient as compared to wild-type mice, together with decreased production of interleukin-10 in all locations except the PP.
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Affiliation(s)
- Lena Ohman
- Department of Clinical Immunology, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden
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Abadía-Molina AC, Mizoguchi A, Faubion WA, De Jong YP, Rietdijk ST, Comiskey M, Clarke K, Bhan AK, Terhorst C. In vivo generation of oligoclonal colitic CD4+ T-cell lines expressing a distinct T-cell receptor Vbeta. Gastroenterology 2005; 128:1268-77. [PMID: 15887110 DOI: 10.1053/j.gastro.2005.01.060] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS Transplantation of wild-type (H-2k) bone marrow into tg epsilon26 mice (BM-->tg epsilon26) induces colitis, characterized by T-helper cell type 1 activation in the lamina propria. Here we determined whether pathogenic T-cell clones could be derived by serial adoptive transfers into healthy tg epsilon26 recipients, starting with the population of CD4+ cells in the mesenteric lymph nodes of BM-->tg epsilon26 mice. METHODS CD4+ cells purified from the mesenteric lymph nodes of colitic BM-->tg epsilon26 mice were adoptively transferred into a second group of healthy tg epsilon26 recipients. Mesenteric lymph node CD4+ cells from the second group of mice were then used for consecutive transfers. Lamina propria CD4+ cells isolated from each mouse with colitis were analyzed for their cytokine profile and for their T-cell receptor Vbeta repertoire. RESULTS CD4+ T cells maintained a dominant T-helper 1 phenotype after multiple transfers (< or = 8) into recipient tg epsilon26 mice. A single T-cell receptor Vbeta was enriched (as much as 90%) in 8 CD4+ T-cell lines: Vbeta8S3, Vbeta8S1/2, Vbeta10S1, or Vbeta14. Sequence analyses of the T-cell receptor Vbetas showed clonality or the presence of a very restricted number of clones within each line. Adoptive transfers of the oligoclonal lines into either C3H x Rag-/- or severe combined immunodeficiency disease mice (H-2k) also induced colitis, whereas transfers into BALB/c x Rag-/- or severe combined immunodeficiency disease mice (H-2d) did not. CONCLUSIONS Colitis-inducing CD4+ T-helper 1 cell clones can be obtained by enrichment through sequential adoptive transfers of CD4+ cells from mesenteric lymph nodes. Distinct dominant T-cell receptor Vbetas in each cell line responded to antigens presented by class II major histocompatibility complex.
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Affiliation(s)
- Ana C Abadía-Molina
- Division of Immunology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
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Zhou P, Borojevic R, Streutker C, Snider D, Liang H, Croitoru K. Expression of dual TCR on DO11.10 T cells allows for ovalbumin-induced oral tolerance to prevent T cell-mediated colitis directed against unrelated enteric bacterial antigens. THE JOURNAL OF IMMUNOLOGY 2004; 172:1515-23. [PMID: 14734729 DOI: 10.4049/jimmunol.172.3.1515] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The triggering Ag for inflammatory bowel disease and animal models of colitis is not known, but may include gut flora. Feeding OVA to DO11.10 mice with OVA-specific transgenic (Tg) TCR generates Ag-specific immunoregulatory CD4(+) T cells (Treg) cells. We examined the ability of oral Ag-induced Treg cells to suppress T cell-mediated colitis in mice. SCID-bg mice given DO11.10 CD4(+)CD45RB(high) T cells developed colitis, and cotransferring DO11.10 CD45RB(low)CD4(+) T cells prevented CD4(+)CD45RB(high) T cell-induced colitis in the absence of OVA. The induction and prevention of disease by DO11.10 CD4(+) T cell subsets were associated with an increase in endogenous TCRalpha chain expression on Tg T cells. Feeding OVA to SCID-bg mice reconstituted with DO11.10 CD4(+)CD45RB(high) attenuated the colitis in association with increased TGF-beta and IL-10 secretion, and decreased proliferative responses to both OVA and cecal bacteria Ag. OVA feeding also attenuated colitis in SCID-bg mice reconstituted with a mix of BALB/c and DO11.10 CD45RB(high) T cells, suggesting that OVA-induced Treg cells suppressed BALB/c effector cells. The expression of endogenous non-Tg TCR allowed for DO11.10-derived T cells to respond to enteric flora Ag. Furthermore, feeding OVA-induced Treg cells prevented colitis by inducing tolerance in both OVA-reactive and non-OVA-reactive T cells and by inducing Ag-nonspecific Treg cells. Such a mechanism might allow for Ag-nonspecific modulation of intestinal inflammation in inflammatory bowel disease.
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MESH Headings
- Administration, Oral
- Adoptive Transfer
- Animals
- Antigens, Bacterial/immunology
- CD4-Positive T-Lymphocytes/immunology
- CD4-Positive T-Lymphocytes/metabolism
- CD4-Positive T-Lymphocytes/transplantation
- Cecum/immunology
- Cecum/microbiology
- Cell Division/genetics
- Cell Division/immunology
- Cell Line
- Colitis/genetics
- Colitis/immunology
- Colitis/pathology
- Colitis/prevention & control
- Cytokines/biosynthesis
- Epitopes, T-Lymphocyte/administration & dosage
- Epitopes, T-Lymphocyte/immunology
- Immune Tolerance/genetics
- Immunity, Mucosal/genetics
- Immunophenotyping
- Intestinal Mucosa/immunology
- Intestinal Mucosa/microbiology
- Intestinal Mucosa/pathology
- Leukocyte Common Antigens/administration & dosage
- Leukocyte Common Antigens/biosynthesis
- Leukocyte Common Antigens/immunology
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, SCID
- Mice, Transgenic
- Ovalbumin/administration & dosage
- Ovalbumin/immunology
- Receptors, Antigen, T-Cell, alpha-beta/biosynthesis
- Receptors, Antigen, T-Cell, alpha-beta/genetics
- Receptors, Interleukin-2/biosynthesis
- T-Lymphocyte Subsets/immunology
- T-Lymphocyte Subsets/metabolism
- T-Lymphocyte Subsets/transplantation
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Affiliation(s)
- Pengfei Zhou
- Intestinal Disease Research Program, Department of Medicine, McMaster University, Hamilton, Ontario L8N 3Z5, Canada
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21
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Ogle BM, Cascalho M, Joao C, Taylor W, West LJ, Platt JL. Direct measurement of lymphocyte receptor diversity. Nucleic Acids Res 2004; 31:e139. [PMID: 14602932 PMCID: PMC275576 DOI: 10.1093/nar/gng139] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
The ability to mount an immune defense against infectious microorganisms and their products, and against tumors is believed to be a direct function of lymphocyte diversity. Because the diversity of lymphocyte receptor genes is >1000-fold more diverse than the entire genome and varies between genetically identical individuals, measuring lymphocyte diversity has been a daunting challenge. We developed a novel technique for measuring lymphocyte diversity directly using gene chips. We reasoned and here demonstrate that the frequency of hybridization of nucleic acids coding for lymphocyte receptors to the oligonucleotides on a gene chip varies in direct proportion to diversity. We applied the technique to detect changes in lymphocyte diversity in mice with known B cell alterations and in persons with known T cell repertoire defects. This approach is the first to provide direct analysis of lymphocyte receptor diversity and should facilitate fundamental study of the adaptive immune system and clinical efforts to assess immunological diseases. In addition, this approach could be more broadly applied, for example to measure diversity of viral quasi-species.
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Affiliation(s)
- Brenda M Ogle
- Transplantation Biology Program, Department of Physiology, Mayo Clinic, Rochester, Minnesota, MN 55905, USA
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22
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Prinz I, Klemm U, Kaufmann SHE, Steinhoff U. Exacerbated colitis associated with elevated levels of activated CD4+ T cells in TCRalpha chain transgenic mice. Gastroenterology 2004; 126:170-81. [PMID: 14699498 DOI: 10.1053/j.gastro.2003.10.062] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
BACKGROUND AND AIMS An unconventional CD4+ TCRalpha(-)beta(+) cell population mediates the development of colitis resembling ulcerative colitis in T-cell receptor alpha mutant (TCRalpha(-/-)) mice. However, the significance of such T cells in individuals with an intact TCRalpha locus remains unclear. Because a substantial proportion of naturally rearranged TCRalpha chains fails to pair with TCRbeta chains, the aim of this study was to analyze the development of CD4+ TCRalpha(-)beta(+) cells and the course of colitis in the presence of such a TCRalpha chain. METHODS TCR chain transgenic TCRalpha(-/-) mice were generated and compared with wild-type and TCRalpha(-/-) mice by flow cytometric analysis of T lymphocytes with respect to their TCR expression and activation status and by histological analysis of colon tissue. The colitogenic potential of the unconventional CD4+ TCRalpha(-)beta(+) cells was assessed by adoptive transfer experiments. Furthermore, the half-life of TCRbeta chains was determined by pulse-chase labeling and immunoprecipitation. RESULTS Transgenic expression of a TCR Valpha7.2 chain led to increased frequencies of CD4+ TCRalpha(-)beta(+) cells that caused rapid onset of colitis, reminiscent of, but even more severe than, that in TCRalpha(-/-) mice. This unconventional T-cell population displayed a constitutively activated phenotype in normal and transgenic TCRalpha(-/-) mice. An extended half-life of newly synthesized TCRbeta chains suggests a chaperone function of the TCR Valpha7.2 chain in TCRalpha(-/-) mice. CONCLUSIONS Physiological TCRalpha rearrangement can promote the formation of chronically activated CD4+ TCRalpha(-)beta(+) T cells and may play a role in the etiology of UC.
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MESH Headings
- Adoptive Transfer
- Animals
- CD4-Positive T-Lymphocytes/metabolism
- Cell Survival
- Colitis/pathology
- Colitis/physiopathology
- Colon/pathology
- Colon/physiopathology
- Gene Rearrangement
- Half-Life
- Lymphocytes
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Mice, Transgenic
- Receptors, Antigen, T-Cell, alpha-beta/chemistry
- Receptors, Antigen, T-Cell, alpha-beta/genetics
- Receptors, Antigen, T-Cell, alpha-beta/metabolism
- Severity of Illness Index
- Thymus Gland/pathology
- Thymus Gland/physiopathology
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Affiliation(s)
- Immo Prinz
- Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany
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23
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Liu L, Wang ZP, Xu CT, Pan BR, Mei QB, Long Y, Liu JY, Zhou SY. Effects of Rheum tanguticum polysaccharide on TNBS -induced colitis and CD4 + T cells in rats. World J Gastroenterol 2003; 9:2284-8. [PMID: 14562394 PMCID: PMC4656479 DOI: 10.3748/wjg.v9.i10.2284] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the effects of Rheum tanguticum polysaccharide-1 (RTP-1) on ulcerative colitis in rats induced by 2, 4, 6-trinitrophene sulphonic acid (TNBS) and their possible mechanism.
METHODS: RTP1 (200 mg·kg-1, ig) extracted from Rheum tanguticum Maxim. ex Regel was administrated to rats with colitis induced by TNBS for 5 d, 7 d, 10 d and 14 d, respectively. The effects of RTP1 and dexamethasone (DX, 0.2 mg·kg-1, ig) were contrastively investigated. The MPO level and SOD activity were determined by chromatometry. The expansion and protein expression of CD4+ T lymphocytes isolated from colon mucosae and mesenteric lymph nodes of colitis rats were performed by immunohistochemical analysis and Western-blot methods.
RESULTS: Treatments of RTP1 (200 mg·kg-1, ig) significantly reduced diarrhea, mortality, colon mass, ulcer areas and MPO level in colon mucosae on days 5, 7, 10 and 14 (5.2 ± 1.4, 5.4 ± 0.7, 5.2 ± 1.8, P < 0.05. 3.4 ± 0.8, P < 0.01. 16.1 ± 12.1, P < 0.01. 31.8 ± 8.6, 17.7 ± 5.3, 12.7 ± 4.1, P < 0.05). The effects of RTP1 were similar to those noted above in DX group, but there were no immunosupressive effects of DX in RTP-1 group, such as body mass loss, thymus and spleen atrophy. The decreased number and down-regulated protein levels of CD4+ T cells isolated from the colon of colitis rats treated with RTP1 were found.
CONCLUSION: RTP1 shows significantly protective effects but lower side effects on rats with colitis induced by TNBS. The mechanism may be due to the resistance to over expansion of CD4.
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Affiliation(s)
- Li Liu
- Department of Pharmacology, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China
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24
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Abstract
The animal models of inflammatory bowel disease provide a framework to define the immunopathogenesis of intestinal inflammation. Studies in these models support the hypothesis that exaggerated immune responses to normal enteric microflora are involved in the initiation and perpetuation of chronic intestinal inflammation. A major pathway involves development of acquired immune responses by the interactions of CD4+ T-cell receptor alphabeta T cells with antigen-presenting cells (dendritic cells). Immunoregulatory cells, including Tr1 cells, Th3 cells, and CD4+ CD25+ T cells and B cells, directly or indirectly affect the T-cell receptor alphabeta T cell-induced immune responses and bridge innate and acquired immunity. The study of these complicated immune networks provides the rationale for the development of new therapeutic interventions in inflammatory bowel disease.
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Affiliation(s)
- Atsushi Mizoguchi
- Department of Pathology, Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, U.S.A
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25
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Boivin GP, Washington K, Yang K, Ward JM, Pretlow TP, Russell R, Besselsen DG, Godfrey VL, Doetschman T, Dove WF, Pitot HC, Halberg RB, Itzkowitz SH, Groden J, Coffey RJ. Pathology of mouse models of intestinal cancer: consensus report and recommendations. Gastroenterology 2003; 124:762-77. [PMID: 12612914 DOI: 10.1053/gast.2003.50094] [Citation(s) in RCA: 395] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Gregory P Boivin
- Department of Pathology and Laboratory Medicine, University of Cincinnati and Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio 45267, USA.
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26
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Abstract
In recent years the status of the inflammatory bowel diseases (IBDs) as canonical autoimmune diseases has risen steadily with the recognition that these diseases are, at their crux, abnormalities in mucosal responses to normally harmless antigens in the mucosal microflora and therefore responses to antigens that by their proximity and persistence are equivalent to self-antigens. This new paradigm is in no small measure traceable to the advent of multiple models of mucosal inflammation whose very existence is indicative of the fact that many types of immune imbalance can lead to loss of tolerance for mucosal antigens and thus inflammation centered in the gastrointestinal tract. We analyze the immunology of the IBDs through the lens of the murine models, first by drawing attention to their common features and then by considering individual models at a level of detail necessary to reveal their individual capacities to provide insight into IBD pathogenesis. What emerges is that murine models of mucosal inflammation have given us a road map that allows us to begin to define the immunology of the IBDs in all its complexity and to find unexpected ways to treat these diseases.
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Affiliation(s)
- Warren Strober
- Mucosal Immunity Section, Laboratory of Clinical Investigation, NIAID, NIH, Bethesda, Maryland 20892-1890, USA.
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27
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Takahashi I, Matsuda J, Gapin L, DeWinter H, Kai Y, Tamagawa H, Kronenberg M, Kiyono H. Colitis-related public T cells are selected in the colonic lamina propria of IL-10-deficient mice. Clin Immunol 2002; 102:237-48. [PMID: 11890710 DOI: 10.1006/clim.2001.5166] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
IL-10 is an important regulatory cytokine in the mucosal immune system, as supported by the fact that mice deficient in IL-10 spontaneously develop Crohn's disease-like colitis. An aberrant, Th1-driven CD4(+) T-cell response to enteric bacteria seems to be important in the pathogenesis of this murine colitis. However, no specific bacteria or bacterial products have been identified, and whether the colitis is mediated by the activation of CD4(+) T cells that recognize specific peptide-MHC complexes is controversial. In this study, we analyzed the TCR beta chain complementarity determining region 3 length spectratype of colonic CD4(+) T cells isolated from diseased IL-10-deficient mice by using the Immunoscope technique. Screening of the diseased interleukin-10-deficient mice resulted in a restricted clonotype in TCR V beta 13 and 14 subfamilies of colonic CD4(+) T cells. In contrast, a Gaussian distribution of clonotype of individual TCR V beta subsets was observed in CD4(+) T cells from the peripheral lymphoid tissues. Although individual variability in the disease-related response was also noted in other IL-10-deficient mice maintained in La Jolla and Osaka, perhaps because of different stages of the disease, genetic background, or the housing environment, colitis-related public clones seemed to be shared in all the diseased mice tested. To address whether public clones were involved, we determined the DNA sequence of the clones. Public motifs were shared in colonic CD4(+) T cells from different background interleukin-10-deficient mice with colitis. The frequently found motifs were SXDWG and SATGNYAEQ. These motifs were not seen in the peripheral lymphoid tissues of diseased mice as well as the colon of non-diseased mice. Thus, the common motif may be related to a public gut-derived antigen, which could be important for the development of pathogenic CD4(+) T cells in this inflammatory bowel disease (IBD) model. The selection of V beta-J beta usage is perhaps stochastic in individual mice; however, the epigenetic generation of SXDWG motif by the recombination machinery and selection for this motif in the gut environment could be important for triggering IBD.
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Affiliation(s)
- Ichiro Takahashi
- Department of Mucosal Immunology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita-Osaka 565-0871, Japan
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28
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Mizoguchi E, Mizoguchi A, Takedatsu H, Cario E, de Jong YP, Ooi CJ, Xavier RJ, Terhorst C, Podolsky DK, Bhan AK. Role of tumor necrosis factor receptor 2 (TNFR2) in colonic epithelial hyperplasia and chronic intestinal inflammation in mice. Gastroenterology 2002; 122:134-44. [PMID: 11781288 DOI: 10.1053/gast.2002.30347] [Citation(s) in RCA: 145] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Tumor necrosis factor (TNF) induces multiple effects including cell proliferation and death by ligation with TNF receptor type II (TNFR2). We studied the role of TNFR2 in chronic inflammation-induced colonic epithelial alteration. METHODS TNFR2 expression in colonic epithelial cells (CECs) was assessed by ribonuclease protection assay (RPA) and immunohistochemistry (IHC) in patients with inflammatory bowel disease (IBD) and murine colitis models. TNFR2 expression was also analyzed using COLO205 cells. The role of TNFR2 in colonic epithelial homeostasis was examined by generating interleukin 6-deficient TCR alpha KO (alpha IL-6DKO) or TNFR2-deficient TCR alpha (alpha TNFR2DKO) mice. RESULTS TNFR2 expression was up-regulated in CEC in both human ulcerative colitis and Crohn's disease. In vitro studies showed that TNFR2 expression was up-regulated by a cooperative effect of key proinflammatory cytokines. By RPA, the increased expression of TNFR2 was detectable in TCR alpha KO mice with colitis compared with TCR alpha KO mice without colitis or wild-type mice. In alpha IL-6DKO mice, TNFR2 expression, proliferation, and nuclear factor kappa B activation of CECs were markedly reduced compared with TCR alpha KO mice. alpha TNFR2 mice also showed significantly less colonic epithelial proliferation compared with TCR alpha KO mice. CONCLUSIONS Expression of TNFR2 is consistently increased on CECs in both murine colitis models as well as patients with IBD. TNFR2 may play an important role in colonic inflammation-associated alteration in the intestinal epithelium.
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MESH Headings
- Animals
- Antigens, CD/genetics
- Antigens, CD/metabolism
- Antimetabolites/pharmacokinetics
- Bromodeoxyuridine/pharmacokinetics
- Cell Line
- Chronic Disease
- Colitis/chemically induced
- Colitis/immunology
- Colitis/pathology
- Colon/immunology
- Colon/pathology
- DNA-Binding Proteins/metabolism
- Dextran Sulfate
- Gene Expression/drug effects
- Gene Expression/immunology
- Genes, T-Cell Receptor alpha/genetics
- Humans
- Hyperplasia
- Indicators and Reagents
- Interleukin-1/pharmacology
- Interleukin-6/genetics
- Interleukin-6/pharmacology
- Intestinal Mucosa/immunology
- Intestinal Mucosa/pathology
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- RNA, Messenger/analysis
- Receptors, Tumor Necrosis Factor/genetics
- Receptors, Tumor Necrosis Factor/metabolism
- Receptors, Tumor Necrosis Factor, Type II
- STAT3 Transcription Factor
- Trans-Activators/metabolism
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Affiliation(s)
- Emiko Mizoguchi
- Center for the Study of Inflammatory Bowel Disease, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
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