A screening system to determine the effect of bacterial metabolites on MAdCAM-1 expression by transformed endothelial sinusoidal cellsTian, Leduc, Fidelle
et alMethods Cell Biol (2025) 194, 119-133
Abstract: Mucosal addressin cell adhesion molecule 1 (MAdCAM-1) expression in high endothelial venules is regulated by bacterial metabolites emanating from the gut and the interaction of MAdCAM-1 with α4β7 integrin mediates lymphocyte diapedesis into gut-associated secondary lymphoid tissues. MAdCAM-1 thus controls the abundance of circulating immunosuppressive T cells that can reach malignant tissue and compromise the therapeutic efficacy of anticancer immunotherapy. Here we describe a biosensor-based phenotypic assessment that facilitates the high throughput screening (HTS)-compatible assessment of MAdCAM-1 regulation in response to exposure to bacterial metabolites. This screening routine encompasses high endothelial venule cells expressing green fluorescent protein (GFP) under the control of the MAdCAM-1 promoter combined with robot-assisted bioimaging and a multistep image analysis pipeline. Altogether this system facilitates the discovery of bacterial composites that control anticancer immunity via the sequestration of Th17-specific regulatory T cells (Treg17) in the gut.Copyright © 2025 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.
Case report: Vedolizumab in Oral Crohn's disease: the downsides of a gut-specific therapy for a multi-site diseaseHarte, Macken, Zou
et alFront Med (Lausanne) (2024) 11, 1485394
Abstract: Crohn's disease (CD) is a chronic inflammatory bowel disease which can affect any area of the gastrointestinal tract, including oral tissues. The complex nature of this disease demands interdisciplinary management, especially when both intestinal and oral manifestations are present.This report presents the case of a 28-year-old male patient with oral, ileo-caecal and peri-anal CD managed jointly between Gastroenterology and Oral Medicine. Treatment with vedolizumab, an α4β7 integrin with gut-selective anti-inflammatory activity, resulted in excellent ileo-caecal disease control, but was ineffective in controlling oral manifestations. The absence of MAdCAM-1 expression in oral tissues, necessary for vedolizumab's mechanism, meant that the drug's anti-inflammatory effects were limited to the gut. This limitation led to worsening oral symptoms, necessitating concomitant azathioprine therapy to manage oral inflammation.Multidisciplinary collaboration is important when managing CD patients with both oral and gut involvement in CD. Clinicians should be aware that vedoluzimab may be beneficial for intestinal CD, but does not target inflammation in oral tissues due to its gut-specific action. Good knowledge of the pharmacology and mechanism of action of drugs prescribed can aid decision making when prescribing for this group of patients and can limit the need for polypharmacy, often associated with an increased adverse effect profile.Copyright © 2024 Harte, Macken, Zou and Fortune.
Mucosal Addressin Cell Adhesion Molecule-1 Mediates T Cell Migration into Pancreas-Draining Lymph Nodes for Initiation of the Autoimmune Response in Type 1 DiabetesLi, Gunderson, Xu
et alInt J Mol Sci (2024) 25 (21)
Abstract: Type 1 diabetes (T1D) is an autoimmune disease that is caused by autoreactive T cell-mediated destruction of insulin-producing β cells in the pancreatic islets. Although naive autoreactive T cells are initially primed by islet antigens in pancreas-draining lymph nodes (pan-LNs), the adhesion molecules that recruit T cells into pan-LNs are unknown. We show that high endothelial venules in pan-LNs of young nonobese diabetic mice have a unique adhesion molecule profile that includes strong expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Anti-MAdCAM-1 antibody blocked more than 80% of the migration of naive autoreactive CD4+ T cells from blood vessels into pan-LNs. Transient blockade of MAdCAM-1 in young nonobese diabetic mice led to increased numbers of autoreactive regulatory CD4+ T cells in pan-LNs and pancreas and to long-lasting protection from T1D. These results indicate the importance of MAdCAM-1 in the development of T1D and suggest MAdCAM-1 as a potential therapeutic target for treating T1D.
Oral reovirus reshapes the gut microbiome and enhances antitumor immunity in colon cancerLee, Lee, Lee
et alNat Commun (2024) 15 (1), 9092
Abstract: The route of oncolytic virotherapy is pivotal for immunotherapeutic efficacy in advanced cancers. In this preclinical study, an oncolytic reovirus (RC402) is orally administered to induce antitumor immunity. Oral reovirus treatment shows no gross toxicities and effectively suppresses multifocal tumor lesions. Orally administered reovirus interacts with the host immune system in the Peyer's patch of the terminal ileum, increases IgA+ antibody-secreting cells in the lamina propria through MAdCAM-1+ blood vessels, and reshapes the gut microbiome. Oral reovirus promotes antigen presentation, type I/II interferons, and T cell activation within distant tumors, but does not reach or directly infect tumor cells beyond the gastrointestinal tract. In contrast to intratumoral reovirus injection, the presence of the gut microbiome, Batf3+ dendritic cells, type I interferons, and CD8+ T cells are indispensable for orally administered reovirus-induced antitumor immunity. Oral reovirus treatment is most effective when combined with αPD-1(L1) and/or αCTLA-4, leading to complete colon tumor regression and protective immune memory. Collectively, oral reovirus virotherapy is a feasible and effective immunotherapeutic strategy in preclinical studies.© 2024. The Author(s).
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