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Overview of the mucosal immune system structure
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Reinhard Pabst, Per Brandtzaeg
In addition, the migration of both T and B cells into, and/or retention within, the small intestinal lamina propria appears to be mediated by the thymus-expressed chemokine (CCL25/TECK). Notably, this chemokine that interacts with CCR9 is selectively produced by the crypt epithelium in this part of the normal gut in humans, as well as mice (Figure 1.8). Several mouse studies have suggested that small intestinal tropism directed by high α4β7 and CCR9 expression combined with minimal CD62L is imprinted on T cells by DCs in PPs and MLNs.
Lymphocyte homing and immunology of extranodal lymphoid tissues
Published in Franco Cavalli, Harald Stein, Emanuele Zucca, Extranodal Lymphomas, 2008
Mariagrazia Uguccioni, James J Campbell, Katrin Kuscher, Marshall E Kadin
Recent studies have demonstrated a critical role of the LN environment for the induction of certain chemokine receptors. Thus, CD8+ and CD4+ T cells are induced to express CCR9 or respond to the CCR9 ligand CCL25, respectively, after activation in mesenteric lymph nodes (MLNs) but not peripheral lymph nodes (PLNs).40,45 The induction of CCR9 and additional chemokine receptors during CD4+ T-cell priming in MLNs and the role of the LN environment in regulating induction of these receptors remain largely uncharacterized.
Controlling in and out – the future of interfering with immune cell trafficking in inflammatory bowel disease
Published in Expert Review of Clinical Immunology, 2023
Sebastian Zundler, Lisa Lou Schulze, Markus F. Neurath
Activated T cells that are destined to home into the gut do not only express α4β7 integrin, but also CCR9, whose ligand is the chemokine C–C motif chemokine ligand 25 (CCL25) [109,110]. CCL25 is primarily expressed in the small intestine and thymus. CCL25/CCR9 signaling has been associated with immune homeostasis, as well as disease and was further shown to promote integrin-mediated lymphocyte adhesion by activation of the integrins α4β7 and α4β1 [111–113]. CCL25 expression was further upregulated in the colons of patients with active UC and correlated with the inflammatory burden [114]. A clinical trial investigating the treatment of patients with UC with CCR9-targeted leukapheresis resulted in the safe and effective removal of activated monocytes and was associated with clinical improvement of those patients [115]. The CCR9-antagonist CCX282-B (vercirnon) was shown to inhibit CCR9-mediated chemotaxis in vitro and in vivo [116]. After promising results in a phase II trial suggesting that vercirnon was safe and effective in inducing clinical response and remission in patients with CD [117], a subsequent phase III trial failed to demonstrate clinical response [118]. Further phase III trials were terminated due to a lack of efficacy (NCT01318993, NCT01316939).
α4β7 integrin inhibitors: a patent review
Published in Expert Opinion on Therapeutic Patents, 2018
Hao Li, Shi-Ying Huang, Fang-Hong Shi, Zhi-Chun Gu, Shun-Guo Zhang, Ji-Fu Wei
Antibodies target on other target on the pathway of T cells homing in the gut may also have application value in the treatment of IBD. PF-00547659 is the first mAb against MAdCAM-1. Results from a randomized placebo-controlled trial show safety and efficacy in patients with active UC after treatment with PF-00547659 [119]. Even no statistical differences are found between actively treated patients and placebo, PF-00547659 produces some potential benefits on clinical and endoscopic efficacy endpoints when compared to placebo [119]. Larger clinical trials evaluating efficacy of PF-00547659 are still needed. A phase Ⅱ, randomized, double-blind, placebo-controlled trial is performed to assess the efficacy and safety of PF-00547659 in patients with moderate to severe UC [120]. PF-00547659 is safe and better than placebo in patients with moderate to severe UC [120]. 22.5 and 75 mg doses of PF-00547659 are observed with the greatest clinical effects [120]. Another phase Ⅱ study evaluates the efficacy of PF-00547659 in the treatment of CD [121]. Clinical endpoint differences between PF-00547659 and placebo dose not reach statistical significance [121]. These results indicate MAdCAM-1 could be a new target for the treatment of IBD [32]. CC-chemokine receptor 9 (CCR9) always co-expresses with α4β7-expressing cells. Directly targeting CCR9 by using the orally administered CCR9 antagonist and α4β7 integrin inhibitor have produced mixed results in the treatment of IBD [122]. These results indicate that MAdCAM-1 and CCR9 are outstanding targets for future research.
Investigational drug therapies for coeliac disease – where to from here?
Published in Expert Opinion on Investigational Drugs, 2018
James Haridy, Diana Lewis, Evan D. Newnham
Similar to α4β7 inhibitors, elevated levels of T-cells expressing the chemokine receptor CCR9, involved in lymphocyte homing to the gastrointestinal mucosa, have been described in CD. In addition, CCR9 is persistently down-regulated on duodenal intraepithelial T-cells in CD, suggesting ongoing epithelial T-cell activation as a therapeutic target [49]. CCX282-B is an orally administered CCR9 antagonist that is currently in Phase 3 trials for IBD. A number of trials with this novel therapeutic have been withdrawn or terminated early for a variety of reasons [50]. A Phase 2 trial in CD had begun enrolment, with 24 subjects recruited in 2007 without any reported adverse effects. However, final outcome data has not been published to date [51].