Antibody Blockade of CCL25/CCR9 Ameliorates Early but not Late Chronic Murine Ileitis

Rivera–Nieves, Jesús; Ho, Johnson; Bamias, Giorgos; Ивашкина, Н. Ю.; Ley, Klaus; Oppermann, Martin; Cominelli, Fabio

doi:10.1053/j.gastro.2006.08.031

Cited by 126 publications

(115 citation statements)

References 44 publications

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“…CCL25 has been acclaimed as a homeostatic chemokine that has also been shown to participate in a few inflammatory processes, mainly in the gut and oral mucosa [25,[27][28][29]. CCR9 + γδ T lymphocytes, which are present in the thymus, peripheral lymph nodes, and spleen, have been shown to be attracted by CCL25 in vitro [6,11,15].…”

Section: Discussionmentioning

confidence: 99%

CCL25 induces α₄β₇ integrin‐dependent migration of IL‐17⁺γδ T lymphocytes during an allergic reaction

Costa¹,

Bornstein²,

Candéa³

et al. 2012

Eur J Immunol

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Herein, we provide evidence that during allergic inflammation, CCL25 induces the selective migration of IL-17 + γδ T cells mediated by α 4 β 7 integrin. Intrapleural injection of CCL25 into ovalbumin (OVA)-immunized C57BL/6 mice triggered the accumulation of γδ T lymphocytes expressing CCR9 (CCL25 receptor) and α 4 β 7 integrin in the pleura, but failed to attract αβ T lymphocytes. CCL25 attracted CCR6 + γδ T cells producing IL-17 (but not IFN-γ or IL-4). OVA challenge triggered increased production of CCL25 followed by the accumulation of CCR9 + , α 4 β 7 + , and CCR6 + /IL-17 + γδ T cells into the pleural cavities of OVA-immunized mice, which was inhibited by the in vivo neutralization of CCL25. The in vivo blockade of α 4 β 7 integrin also inhibited the migration of IL-17 + γδ T lymphocytes (but not of αβ T lymphocytes) into mouse pleura after OVA challenge, suggesting that the CCL25/α 4 β 7 integrin pathway is selective for γδ T cells. In addition, α 4 β 7 integrin blockade impaired the in vitro transmigration of γδ T cells across endothelium (which expresses α 4 β 7 ligands VCAM-1 and MadCAM-1), which was induced by CCL25 and by cell-free pleural washes recovered from OVA-challenged mice. Our results reveal that during an allergic reaction, CCL25 drives IL-17 + γδ T-cell mobilization to inflamed tissue via α 4 β 7 integrin and modulates IL-17 levels. Keywords: Adhesion molecules IntroductionLymphocytes bearing the γδ T-cell receptor (TCR) comprise a minor T-lymphocyte subset in blood and secondary lymphoid tissues and are preferentially localized in epithelial and mucosal tissues [1,2]. This unique subset of lymphocytes can provide rapid tissue-specific immune responses, without the requirement of antiCorrespondence: Dr. Carmen Penido e-mail: cpenido@far.fiocruz.br gen presentation or clonal expansion, and is able to produce a large repertory of Th1-, Th2-, and Th17-associated cytokines [2][3][4][5][6]. These characteristics make γδ T cells a crucial first line of defense during infection, tissue damage, or stress.γδ T cells have been shown to migrate into the airways during allergic inflammation highly controlled by a chemotactic gradient of chemokines produced in tissue [5,[7][8][9][10][11]. We have previously demonstrated that allergen-induced γδ T-cell accumulation is * These authors contributed equally to this work.www.eji-journal.eu Eur. J. Immunol. 2012. 42: 1250-1260 Immunomodulation 1251 paralleled with a marked production of chemokines in the tissue, including CCL25/TECK [11]. CCL25 is mostly described as a homeostatic chemokine that plays a major role in T-cell development in the thymus and in intraepithelial lymphocytes (IELs) homing into small intestine mucosa [12]. Recent data have provided evidence that CCL25 production increases during inflammatory processes that take place at nonmucosal tissues, such as autoimmune arthritis, atherosclerosis, and allergy [11,13,14]. Moreover, we and others have shown that γδ T lymphocytes migrate in vitro toward CCL25, via its counterpart receptor CCR9 [11,...

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Section: Discussionmentioning

confidence: 99%

CCL25 induces α₄β₇ integrin‐dependent migration of IL‐17⁺γδ T lymphocytes during an allergic reaction

Costa¹,

Bornstein²,

Candéa³

et al. 2012

Eur J Immunol

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“…In a mouse model of colitis, the sites of inflammation coincide with the with the location of CCL25 expression and the number of CCR9 + T-cells increases with disease progression reaching a peak at the time point when most severe inflammation can be observed [173]. However, in this model of inflammation, blockade of either CCL25 or CCR9 was only effective in early stages of the disease development [174]. In a further colitis mouse model, deficiency of CCL25 or CCR9 did not have any effect on disease development or progression [175].…”

Section: Anti-c-c Chemokine Receptor Type 9 (Ccr9)mentioning

confidence: 99%

Review: New Anti-Cytokines for IBD: What is in the Pipeline?

Scharl

Vavricka²,

Rogler

2013

CDT

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Significant advances have been achieved in the understanding of the pathogenesis of inflammatory bowel disease (IBD). A number of susceptibility genes have been detected by large genome wide screening-approaches. New therapeutic concepts emerge from these insights. The most important progress in recent years certainly is the introduction of biologics in the therapy of IBD. TNF blockers have been shown to be very effective for the control of complicated disease courses. Currently, in addition to the three already established anti-TNF antibodies, new anti-TNF molecules, for example Golimumab, are in clinical trials and also reveal promising results. However, not all of the patients respond to anti-TNF treatment and many patients lose their response. Therefore, additional therapeutic approaches are urgently needed. Attractive therapy targets are cytokines as well as their receptors and signaling pathways. At the moment a large number of biologicals and inhibitors are tested in clinical trials and some of them provide very promising results for the treatment of IBD patients. In particular, inhibition of IL-12p40 by specific antibodies as well as of the janus kinase (JAK)3 by a small molecule promise to be very effective approaches. Though antibodies targeting for example IL-6, IL-6R, IL-13 or CCR9 are only in the early steps of clinical development, they have already demonstrated to be a possible treatment option which needs to be confirmed in further trials. Taken together a large number of new therapeutic anti-cytokine approaches are currently tested in clinical trials in IBD patients. In this review, the new therapeutic approaches for cytokine inhibition in IBD patients are discussed. Taken together a large number of new therapeutic anti-cytokine approaches are currently tested in clinical trials in IBD patients. In this review, the new therapeutic approaches for cytokine inhibition in IBD patients are discussed.

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“…† Despite these findings, CCR9 Ϫ/Ϫ mice have relatively normal numbers of small intestinal CD8␣␤ ϩ and CD4 ϩ T cells (12)(13)(14). Furthermore, antibodies to CCR9 and CCL25 only partially ameliorate early but note late chronic murine ileitis (15). Thus, a clearer understanding of the relative roles of CCR9-dependent and independent T cell entry to and localization within the intestinal mucosa is warranted.…”

mentioning

confidence: 99%

Differential homing mechanisms regulate regionalized effector CD8αβ ⁺ T cell accumulation within the small intestine

Stenstad

Svensson

Cucak

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The CC chemokine receptor (CCR)9 is expressed on the majority of small intestinal, but few colonic, T cells, whereas its ligand CCL25 is constitutively expressed by small intestinal epithelial cells. As such, CCR9/CCL25 have been proposed to play a central role in regulating small intestinal but not colonic immune responses and thus to organize regionalized immunity within the intestinal mucosa. Here, we demonstrate that CCL25 is expressed at reduced levels by epithelial cells in the distal compared with proximal small intestine, which correlated with less efficient CCR9-dependent effector CD8␣␤ ؉ T cell entry into the ileal epithelium. In vitro-generated ␣4␤7 ؉ effector CD8␣␤ ؉ T cell entry into the lamina propria was less dependent on CCR9 than entry into the epithelium along the entire length of the small intestine and in particular in the ileum. CCR9-independent ␣4␤7 ؉ effector CD8␣␤ ؉ T cell entry was pertussis toxin-sensitive, suggesting a role for additional G␣ I-linked G protein-coupled receptors. Finally, in vivo-primed effector CD8␣␤ ؉ T cells displayed regionalized differences in their entry to the small intestinal epithelium with enhanced CCR9-independent entry to the ileum. These results highlight a hitherto underappreciated compartmentalization of immune responses within the small intestine and have direct implications for targeting strategies aimed at regulating T cell localization to the small intestinal mucosa.chemokine receptor ͉ intestinal mucosa

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Antibody Blockade of CCL25/CCR9 Ameliorates Early but not Late Chronic Murine Ileitis

Cited by 126 publications

References 44 publications

CCL25 induces α₄β₇ integrin‐dependent migration of IL‐17⁺γδ T lymphocytes during an allergic reaction

CCL25 induces α₄β₇ integrin‐dependent migration of IL‐17⁺γδ T lymphocytes during an allergic reaction

Review: New Anti-Cytokines for IBD: What is in the Pipeline?

Differential homing mechanisms regulate regionalized effector CD8αβ ⁺ T cell accumulation within the small intestine

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Antibody Blockade of CCL25/CCR9 Ameliorates Early but not Late Chronic Murine Ileitis

Cited by 126 publications

References 44 publications

CCL25 induces α4β7 integrin‐dependent migration of IL‐17+γδ T lymphocytes during an allergic reaction

CCL25 induces α4β7 integrin‐dependent migration of IL‐17+γδ T lymphocytes during an allergic reaction

Review: New Anti-Cytokines for IBD: What is in the Pipeline?

Differential homing mechanisms regulate regionalized effector CD8αβ + T cell accumulation within the small intestine

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CCL25 induces α₄β₇ integrin‐dependent migration of IL‐17⁺γδ T lymphocytes during an allergic reaction

CCL25 induces α₄β₇ integrin‐dependent migration of IL‐17⁺γδ T lymphocytes during an allergic reaction

Differential homing mechanisms regulate regionalized effector CD8αβ ⁺ T cell accumulation within the small intestine