The role of integrins in the pathogenesis of inflammatory bowel disease: Approved and investigational anti‐integrin therapies

Dotan, Iris; Allez, Matthieu; Danese, Silvio; Keir, Mary E.; Tole, Swati; McBride, Jacqueline

doi:10.1002/med.21601

Cited by 63 publications

(49 citation statements)

References 136 publications

(269 reference statements)

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“…Finally, additional integrins might be important as well for gut-specific migration, including αEβ7. 30 A B (bottom panel) memory T cells in control subjects, patients with UC and those with CD. For TRBV figures depict only genes with >1% frequency.…”

Section: Discussionmentioning

confidence: 99%

Circulating α4β7+ Memory T Cells in Pediatric IBD Patients Express a Polyclonal T Cell Receptor Repertoire

Gamliel

Werner

Pinsker

et al. 2020

CEG

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Background: The integrin α4β7 is highly expressed on activated T cells and is thought to direct homing of lymphocytes to the intestine. Since ulcerative colitis (UC) and Crohn's disease (CD) are characterized by mucosal oligoclonal T cells' expansion, we aimed to assess whether similar repertoire features are identified in circulating gut-specific memory T cells. Methods: Memory CD3 + T cells were isolated from blood samples of control subjects and patients with active UC or CD and then FACS-sorted into α4β7 + and α4β7 − populations. DNA was extracted from each subset and subjected to next-generation sequencing of the TCRβ. Different repertoire characteristics were compared between α4β7 + and α4β7 − subsets for each subject, and between groups. Results: The percentages of memory T cells and α4β7 + cells were comparable between groups. α4β7 + memory T cells displayed a polyclonal distribution, in control subjects and in UC or CD patients, with similar indices of diversity. Strikingly, the clonal overlap between α4β7 + and α4β7 − T cells for each subject in all three groups was high, ranging between 20%-50%. We were unable to identify shared T cell clones that were specific to one of the groups. Conclusion: α4β7 + memory T cells exhibited a polyclonal repertoire in both control subjects and patients with active inflammatory bowel disease, with high rates of overlap with α4β7 − memory T cells. Our study, along with additional recent reports, may suggest that the suppression of intestinal inflammation by vedolizumab is independent of the drug's effect on T cell migration to the gut.

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Section: Discussionmentioning

confidence: 99%

Circulating α4β7+ Memory T Cells in Pediatric IBD Patients Express a Polyclonal T Cell Receptor Repertoire

Gamliel

Werner

Pinsker

et al. 2020

CEG

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“… 75 Interactions between integrin integrin alpha 4 beta 7 and the microvascular cell-adhesion molecule MAdCAM-1 or between integrin integrin alpha 4 beta 1 and the microvascular cell-adhesion molecule VCAM-1 can induce chronic inflammation in the gut, leading to the migration of T-lymphocytes and the production of inflammatory mediators, such as interleukin-17 or interferon-γ. 76 In patients with IBD, there is an upregulation of the microvascular cell-adhesion molecules ICAM-1, VCAM-1, and MadCAM-1 77 , leading to an increased recruitment of α4 integrin-expressing leukocytes. On the other hand, in a recent study using a mouse model of IBD, the genetic deletion of the β7 integrin or the antibody blockade of an α4β7-MAdCAM-1 interaction worsened colitis.…”

Section: Ace2 As a Ligand For Integrins—a Mechanism Of Fibrosis In Ibmentioning

confidence: 99%

Unraveling the Role of ACE2, the Binding Receptor for SARS-CoV-2, in Inflammatory Bowel Disease

Ferreira‐Duarte

Estevinho

Duarte‐Araújo

et al. 2020

Inflammatory Bowel Diseases

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Angiotensin-converting enzyme 2 (ACE2) has been highlighted for its role as a receptor for SARS-CoV-2, responsible for the current COVID-19 pandemic. This review summarizes current knowledge about ACE2 as a multifunctional protein, focusing on its relevance in inflammatory bowel disease (IBD). As an enzyme, ACE2 may be protective in IBD because it favors the counter-regulatory arm of the renin-angiotensin system or deleterious because it metabolizes other anti-inflammatory/repairing elements. Meanwhile, as a receptor for SARS-CoV-2, the impact of ACE2 expression/activity on infection is still under debate because no direct evidence has been reported and, again, both protective and deleterious pathways are possible. Research has shown that ACE2 regulates the expression of the neutral amino acid transporter B0AT1, controlling tryptophan-associated intestinal inflammation and nutritional status. Finally, intact membrane-bound or shed soluble ACE2 can also trigger integrin signaling, modulating the response to anti-integrin biologic drugs used to treat IBD (such as vedolizumab) and fibrosis, a long-term complication of IBD. As such, future studies on ACE2 expression/activity in IBD can improve monitoring of the disease and explore an alternative pharmacological target.

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“…In contrast, RGD peptides may bind to multiple integrins at sites of different overall structure that recognize the RGD sequence. Integrin antagonists demonstrated a wide range of therapeutic applications in thrombosis, vascular restenosis, cancer, asthma, allergy, and inflammatory diseases (Desgrosellier and Cheresh 2010;Dotan et al 2020;Raab-Westphal et al 2017).…”

Section: Anti-integrinmentioning

confidence: 99%

“…Anti-integrins, Fig. 1 Diagrammatic representation of integrin inside-out signaling and integrin activation, which require conformational switch from bent-closed or extended-closed to extended-open confirmation substantial for possible application to inflammatory states, such as inflammatory bowel disease (Dotan et al 2020;Park and Jeen 2018;Sabino et al 2019;Shah et al 2017). Integrins other than avb3 have also been linked to cancer (Seguin et al 2015;Desgrosellier and Cheresh 2010;Raab-Westphal et al 2017).…”

Section: Integrin-focused Drug Development Has Beenmentioning

confidence: 99%

Anti-integrins

Mousa¹,

Davis²

2020

Encyclopedia of Molecular Pharmacology

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The role of integrins in the pathogenesis of inflammatory bowel disease: Approved and investigational anti‐integrin therapies

Cited by 63 publications

References 136 publications

<p>Circulating α4β7<sup>+</sup> Memory T Cells in Pediatric IBD Patients Express a Polyclonal T Cell Receptor Repertoire</p>

<p>Circulating α4β7<sup>+</sup> Memory T Cells in Pediatric IBD Patients Express a Polyclonal T Cell Receptor Repertoire</p>

Unraveling the Role of ACE2, the Binding Receptor for SARS-CoV-2, in Inflammatory Bowel Disease

Anti-integrins

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