The α4β1 Homing Pathway is Essential for Ileal Homing of Crohn's Disease Effector T Cells in vivo

Zundler, Sebastian; Fischer, Anika; Schillinger, Daniela; Binder, Marie-Theres; Atreya, Raja; Räth, Timo; López-Posadas, Rocío; Voskens, Caroline J.; Watson, Alastair; Atreya, Imke; Neufert, Clemens

doi:10.1016/s0016-5085(17)30841-7

Cited by 25 publications

(35 citation statements)

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“…This strategy may target the migration of leukocytes into the inflamed tissue by combining their mechanisms of action, as peripheral inflammatory cells affected by VDZ may be removed by the ability of GMA to adsorb multiple immune cells. This hypothesis is based in part on the observation of an increase in some subpopulations of peripheral lymphocytes (especially Treg) within the first weeks of VDZ treatment . Based on these findings, this approach may appear as an alternative strategy for some patients during the induction period or after a LOR to VDZ.…”

Section: Discussionmentioning

confidence: 99%

The combination of granulocyte‐monocyte apheresis and vedolizumab: A new treatment option for ulcerative colitis?

Rodríguez‐Lago

Benítez

Sempere

et al. 2019

J of Clinical Apheresis

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Objectives To assess the effectiveness and safety of combining granulocyte‐monocyte apheresis (GMA) and vedolizumab (VDZ) in patients with refractory ulcerative colitis (UC). Methods This retrospective, multicentre pilot study included all UC patients receiving both GMA and VDZ. We recorded data on GMA sessions, demographic characteristics, and clinical response. Effectiveness was assessed 1 and 6 months after finishing the GMA using the partial Mayo score, C‐reactive protein, and fecal calprotectin levels. Data were also compiled on VDZ intensification, use of new immunomodulators and colectomy during follow‐up. Results Eight patients were included (mean age 46 years; 63% female; mean disease duration, 132 months; 50% E3). GMA was started after a loss of response to VDZ in all cases (25% primary nonresponse and 75% secondary loss of response). All had previously received anti‐TNF agents. VDZ was prescribed as the second‐, third‐, or fourth‐line biologic in 37%, 50%, and 13% of cases, respectively. Patients had a mean baseline partial Mayo score of 7.5 (SD 2.1) and received a median of 15 GMA sessions (range 5‐38). After a median follow‐up of 7.5 months (IQR 5‐12), partial Mayo score decreased after 1 and 6 months (P = .01 and .06, respectively). Three patients (38%) achieved steroid‐free clinical remission and five (63%) withdrew VDZ. Colectomy rate was 38%. No adverse events were observed during the combination therapy. Conclusions This small case series suggests that combining GMA with VDZ could be a treatment option in selected cases of UC with an inadequate response to this biologic agent.

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Section: Discussionmentioning

confidence: 99%

The combination of granulocyte‐monocyte apheresis and vedolizumab: A new treatment option for ulcerative colitis?

Rodríguez‐Lago

Benítez

Sempere

et al. 2019

J of Clinical Apheresis

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“…Fischer et al reported that in a humanized mouse model of colitis, vedolizumab inhibited the homing of UC T eff cells and T reg cells to the mouse colon. A subsequent publication from the same group showed that vedolizumab had only marginal effects on homing of CD T eff cells to the ileum, whereas natalizumab reduced CD T eff cell homing . These data suggest that inhibition of α4β7‐dependent homing of CD T eff cells may be bypassed by a compensatory homing mechanism through α4β1:VCAM‐1, which is supported by the increased α4β1 expression on T eff cells from patients with CD.…”

Section: A Model For Integrins and T Lymphocytes As Therapeutic Targementioning

confidence: 91%

“…Although α4β1 and α4β7 are both expressed in humans at low levels on naive T lymphocytes, CD4 + T mem lymphocytes can express high levels of either α4β1 or α4β7 integrin, or both integrins . α4β1:VCAM may be able to drive intestinal homing independently of α4β7/MAdCAM under some conditions . The majority of gut homing is likely facilitated through the interaction between α4β7 integrin and MAdCAM‐1, which is constitutively expressed in intestinal tissue and increased in IBD .…”

Section: Immune Cell Functions In the Gut And Ibdmentioning

confidence: 99%

“…These data suggest that inhibition of α4β7‐dependent homing of CD T eff cells may be bypassed by a compensatory homing mechanism through α4β1:VCAM‐1, which is supported by the increased α4β1 expression on T eff cells from patients with CD. Results from these two studies suggest that the underlying pathologic and trafficking mechanisms within CD versus UC may differ at the cellular level and could perhaps explain the trend towards greater improvements with vedolizumab treatment in patients with UC compared with CD . The relative importance of α4β7 and α4β1 integrin expression on trafficking of pro‐inflammatory T lymphocytes between UC and CD remains to be fully elucidated.…”

Section: A Model For Integrins and T Lymphocytes As Therapeutic Targementioning

confidence: 99%

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

Dotan

Allez

Danese

et al. 2019

Medicinal Research Reviews

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Inflammatory bowel disease (IBD) is characterized by uncontrolled inflammation in the gastrointestinal tract. The underlying pathobiology of IBD includes an increase in infiltrating gut‐homing lymphocytes. Although lymphocyte homing is typically a tightly regulated and stepwise process involving multiple integrins and adhesion molecules expressed on endothelial cells, the distinct roles of integrin‐expressing immune cells is not fully understood in the pathology of IBD. In this review, we detail the involvement of integrins expressed on specific lymphocyte subsets in the pathogenesis of IBD and discuss the current status of approved and investigational integrin‐targeted therapies.

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“…In conclusion, T cell priming in the GALT leads to the specific generation of large numbers of antigen‐specific T cells capable to home to the gut. After such T cells have left the GALT to recirculate in the blood stream, this takes places in intestinal HEVs by rolling through low‐affinity α4β7‐MAdCAM‐1 interactions, CCL‐25‐dependent activation via CCR9 and finally firm arrest mediated again by α4β7‐MAdCAM‐1 or α4β1‐vascular cell adhesion molecule (VCAM)‐1 . After transmigration these T cells have then reached their provisional destination and are ready to contribute to immunologic events.…”

Section: How T Cells Reach and Stay In The Gut: Overview Of T Cell Trmentioning

confidence: 99%

Pathogenic T cell subsets in allergic and chronic inflammatory bowel disorders

Zundler

Neurath

2017

Immunological Reviews

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Homeostasis in the gastrointestinal tract relies on a sensitive equilibrium between permissive and protective functions. This is closely reflected in the regulation of the intestinal immune system and especially T cells in the gut. This balance, however, is susceptible to disturbances as demonstrated by pathological conditions like food allergy, celiac disease, or inflammatory bowel disease. In these allergic and chronic inflammatory bowel disorders, luminal antigens get access to the lamina propria where they trigger a dysregulated immune response with crucial involvement of different T cell subsets. We will begin this review with some comprehensive remarks on current concepts on the pathogenesis of these diseases before taking a closer look at the life cycle of intestinal T cells consisting of priming, homing, differentiation and proliferation and apoptosis respectively. Subsequently we will discuss the specific implication of distinct T cell subsets in allergic and chronic inflammatory conditions of the gastrointestinal tract in detail and comment on current and future approaches to targeted therapy in this context.

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The α4β1 Homing Pathway is Essential for Ileal Homing of Crohn's Disease Effector T Cells in vivo

Cited by 25 publications

References 0 publications

The combination of granulocyte‐monocyte apheresis and vedolizumab: A new treatment option for ulcerative colitis?

The combination of granulocyte‐monocyte apheresis and vedolizumab: A new treatment option for ulcerative colitis?

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

Pathogenic T cell subsets in allergic and chronic inflammatory bowel disorders

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