Differential expression of mucosal addressin cell adhesion molecule‐1 (MAdCAM‐1) in ulcerative colitis and Crohn's disease

Arihiro, Seiji; Ohtani, Haruo; Suzuki, Manabu; Morimoto, Masahiro; Ejima, Chieko; Oki, Motoji; Kinouchi, Yoshitaka; Fukushima, Kouhei; Sasaki, Iwao; Nakamura, Shirô; Matsumoto, Takayuki; Torii, Akihiro; Toda, Gotaro; Nishimura, Hiroshi

doi:10.1046/j.1440-1827.2002.01365.x

Cited by 129 publications

(75 citation statements)

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“…The causes of extraintestinal manifestations in IBD are poorly understood. Such extraintestinal manifestations may be a consequence of dysregulation in lymphocyte-homing pathways [37][38][39]. In agreement, our findings demonstrate the effect of tissue microenvironment in controlling DC phenotype and function, and provide an explanation for development of extraintestinal manifestations in UC patients due to a dysregulated homing response.…”

supporting

confidence: 86%

IL‐6 promotes immune responses in human ulcerative colitis and induces a skin‐homing phenotype in the dendritic cells and Tcells they stimulate

et al. 2012

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Dendritic cells (DCs) control the type and location of immune responses. Ulcerative colitis (UC) is considered a Th2 disease mediated by IL-13 where up to one third of patients can develop extraintestinal manifestations. Colonic biopsies from inflamed and noninflamed areas of UC patients were cultured in vitro and their supernatants were used to condition human blood enriched DCs from healthy controls. Levels of IL-13 in the culture supernatants were below the detection limit in most cases and the cytokine profile suggested a mixed profile rather than a Th2 cytokine profile. IL-6 was the predominant cytokine found in inflamed areas from UC patients and its concentration correlated with the Mayo endoscopic score for severity of disease. DCs conditioned with noninflamed culture supernatants acquired a regulatory phenotype with decreased stimulatory capacity. However, DCs conditioned with inflamed culture supernatants acquired a proinflammatory phenotype with increased expression of the skin-homing chemokine CCR8. These DCs did not have decreased T-cell stimulatory capacity and primed T cells with the skin-homing CLA molecule in an IL-6-dependent mechanism. Our results highlight the role of IL-6 in UC and question the concept of UC as a Th2 disease and the relevance of IL-13 in its etiology.Keywords: Dendritic cells r IL-6 r Mucosal immunity r Intestinal immunity r Ulcerative colitis Correspondence: Prof. Stella C. Knight e-mail: s.knight@imperial.ac.uk IntroductionThe gastrointestinal tract is in contact with a wide variety of commensal microbiota and diverse pathogens, and therefore C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 1338 David Bernardo et al. Eur. J. Immunol. 2012. 42: 1337-1353 requires a balance to be maintained between immunity and immune tolerance; the lack of immune responses against food antigens and/or the commensal microbiota is essential to maintain the homeostasis of the gastrointestinal tract [1]. Ulcerative colitis (UC) is a form of inflammatory bowel disease (IBD), traditionally related to a Th2 cytokine profile mediated by 3], where immune homeostasis of the gastrointestinal tract is compromised. Up to 1/3rd of UC patients can develop extraintestinal manifestations with the skin being one of such tissues [4,5].Dendritic cells (DCs) are the most potent antigen presenting cells and determine the nature and type of immune responses [6,7]. Intestinal DCs control immune tolerance in the gastrointestinal tract [8][9][10]. DCs also maintain immune responses localized to specific tissues, since they imprint specific tissue-homing profiles on stimulated T cells [11]. Retinoic acid (RA), the active form of vitamin A following dehydrogenization by the RALDH2 enzyme controls some of the mechanisms of immune homeostasis of the gut [12][13][14]. RA-producing DCs mediate the IgA switching of B cells [15], the generation of T cells with a regulatory phenotype [10], and the imprinting of gut-homing markers on B and T cells [16,17], thereby keeping tolerogenic immune responses com...

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confidence: 86%

IL‐6 promotes immune responses in human ulcerative colitis and induces a skin‐homing phenotype in the dendritic cells and Tcells they stimulate

et al. 2012

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“…The α4β7 integrin [22] , a cell surface glycoprotein variably expressed on circulating B and T lymphocytes, interacts with mucosal addressin-cell adhesion molecule 1 (MAdCAM-1) [23] on the intestinal vasculature [24,25] . Vedolizumab, a humanized monoclonal antibody that specifically recognizes the α4β7 heterodimer, selectively blocks gut lymphocyte trafficking without interfering with trafficking to the central nervous system [26][27][28] (Figure 1).…”

Section: Vedolizumabmentioning

confidence: 99%

Promising biological therapies for ulcerative colitis: A review of the literature

Akiho¹,

Yokoyama²,

Abe³

et al. 2015

WJGP

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Ulcerative colitis (UC) is a chronic lifelong condition characterized by alternating flare-ups and remission. There is no single known unifying cause, and the pathogenesis is multifactorial, with genetics, environmental factors, microbiota, and the immune system all playing roles. Current treatment modalities for UC include 5-aminosalicylates, corticosteroids, immunosuppressants (including purine antimetabolites, cyclosporine, and tacrolimus), and surgery. Therapeutic goals for UC are evolving. Medical treatment aims to induce remission and prevent relapse of disease activity. Infliximab, an anti-tumor necrosis factor (TNF)-α monoclonal antibody, is the first biological agent for the treatment of UC. Over the last decade, infliximab and adalimumab (anti-TNF-α agents) have been used for moderate to severe UC, and have been shown to be effective in inducing and maintaining remission. Recent studies have indicated that golimumab (another anti-TNF-α agent), tofacitinib (a Janus kinase inhibitor), and vedolizumab and etrolizumab (integrin antagonists), achieved good clinical remission and response rates in UC. Recently, golimumab and vedolizumab have been approved for UC by the United States Food and Drug Administration. Vedolizumab may be used as a first-line alternative to anti-TNF-α therapy in patients with an inadequate response to corticosteroids and/or immunosuppressants. Here, we provide updated information on various biological agents in the treatment of UC.Key words: Ulcerative colitis; Biological therapy; Antitumor necrosis factor α agents; Janus kinase inhibitor; Anti-integrin agents

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“…214 MAdCAM-1 expression is upregulated in the intestine in animal models of colitis [215][216][217][218][219] and in human IBD. 220,221 Alterations in the number and function of a4b7 hi and CCR9 þ gut-homing cells occur in both active CD and UC. [220][221][222] Therapeutic interventions targeting a4b7, a4, MAdCAM-1, and CCR9 show benefit in experimental models or human clinical trials, [223][224][225][226][227] confirming that recruitment of leukocyte populations to the intestine is a critical step in the disease process.…”

Section: Control Of Lymphocyte Homing In the Inflamed Intestine Anmentioning

confidence: 99%

Intestinal dendritic cells

Kamm

Stagg

et al. 2010

Inflammatory Bowel Diseases

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Dendritic cells (DCs) play a key role in discriminating between commensal microorganisms and potentially harmful pathogens and in maintaining the balance between tolerance and active immunity. The regulatory role of DC is of particular importance in the gut where the immune system lies in intimate contact with the highly antigenic external environment. Intestinal DC constantly survey the luminal microenvironment. They act as sentinels, acquiring antigens in peripheral tissues before migrating to secondary lymphoid organs to activate naive T cells. They are also sensors, responding to a spectrum of environmental cues by extensive differentiation or maturation. Recent studies have begun to elucidate mechanisms for functional specializations of DC in the intestine that may include the involvement of retinoic acid and transforming growth factor-β. Specialized CD103(+) intestinal DC can promote the differentiation of Foxp3(+) regulatory T cells via a retinoic acid-dependent process. Different DC outcomes are, in part, influenced by their exposure to microbial stimuli. Evidence is also emerging of the close interaction between bacteria, epithelial cells, and DC in the maintenance of intestinal immune homeostasis. Here we review recent advances of functionally specialized intestinal DC and their mechanisms of antigen uptake and recognition. We also discuss the interaction of DC with intestinal microbiota and their ability to orchestrate protective immunity and immune tolerance in the host. Lastly, we describe how DC functions are altered in intestinal inflammation and their emerging potential as a therapeutic target in inflammatory bowel disease.

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Differential expression of mucosal addressin cell adhesion molecule‐1 (MAdCAM‐1) in ulcerative colitis and Crohn's disease

Cited by 129 publications

References 33 publications

IL‐6 promotes immune responses in human ulcerative colitis and induces a skin‐homing phenotype in the dendritic cells and Tcells they stimulate

IL‐6 promotes immune responses in human ulcerative colitis and induces a skin‐homing phenotype in the dendritic cells and Tcells they stimulate

Promising biological therapies for ulcerative colitis: A review of the literature

Intestinal dendritic cells

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