Dual targeting of lymphocyte homing and retention through α4β7 and αEβ7 inhibition in inflammatory bowel disease
| Autor: | Tangsheng Yi, Allen Nguyen, Azra Hassanali, Bingbing Dai, Kai-Hui Sun, Swati Tole, Jason A. Hackney, Mary E. Keir, Jacqueline McBride, Luz D. Orozco, Young S Oh, Akiko Chai, Aida Habtezion, Alexis Scherl, John Gubatan, Monika Deswal, Justin Elstrott, Zaineb Sharafali, Alvin Gogineni, Ma Somsouk, Ryan Ichikawa, William A. Faubion, Zora Modrusan |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Integrins
Cytotoxic Lymphocyte T-Lymphocytes Biopsy Crohn's Disease T cell entry and retention Cell Communication CD8-Positive T-Lymphocytes Inbred C57BL Inflammatory bowel disease Transgenic Oral and gastrointestinal etrolizumab Mice Epitopes Cell Movement Monoclonal Medicine Cytotoxic T cell 2.1 Biological and endogenous factors Lymphocytes Aetiology Intestinal Mucosa Humanized Cadherins α4β7 medicine.anatomical_structure 5.1 Pharmaceuticals Female Development of treatments and therapeutic interventions αEβ7 Colon T cell Mice Transgenic Antibodies Monoclonal Humanized Autoimmune Disease General Biochemistry Genetics and Molecular Biology Antibodies Article inflammatory bowel disease Animals Lymphocyte homing receptor Inflammation business.industry Inflammatory and immune system medicine.disease Inflammatory Bowel Diseases Blockade Mice Inbred C57BL Gene Expression Regulation Cancer research Intraepithelial lymphocyte Lymph Nodes business Digestive Diseases CD8 T-Lymphocytes Cytotoxic |
| Zdroj: | Cell Reports Medicine Cell reports. Medicine, vol 2, iss 8 |
| ISSN: | 2666-3791 |
| Popis: | Summary Anti-integrins are therapeutically effective for inflammatory bowel disease, yet the relative contribution of α4β7 and αEβ7 to gut lymphocyte trafficking is not fully elucidated. Here, we evaluate the effect of α4β7 and αEβ7 blockade using a combination of murine models of gut trafficking and longitudinal gene expression analysis in etrolizumab-treated patients with Crohn's disease (CD). Dual blockade of α4β7 and αEβ7 reduces CD8+ T cell accumulation in the gut to a greater extent than blockade of either integrin alone. Anti-αEβ7 reduces epithelial:T cell interactions and promotes egress of activated T cells from the mucosa into lymphatics. Inflammatory gene expression is greater in human intestinal αEβ7+ T cells. Etrolizumab-treated patients with CD display a treatment-specific reduction in inflammatory and cytotoxic intraepithelial lymphocytes (IEL) genes. Concurrent blockade of α4β7 and αEβ7 promotes reduction of cytotoxic IELs and inflammatory T cells in the gut mucosa through a stepwise inhibition of intestinal tissue entry and retention. Graphical abstract Highlights Blockade of α4β7 and αEβ7 reduces CD8+ T cells in the gut mucosa more than α4β7 alone Anti-αEβ7 or -E-cadherin reduces retention and increases egress of T cells in the gut αEβ7+ intestinal T cells are proinflammatory and have little to no regulatory markers Etrolizumab reduces mucosal inflammatory T cell genes in patients with Crohn disease Dai et al. demonstrate the cooperative roles α4β7 and αEβ7 integrins have in CD8+ T cell accumulation in the gut mucosa in a mouse model of trafficking. Intestinal biopsies from patients with Crohn disease that has been treated with etrolizumab (anti-β7) show treatment-specific reductions in gene expression associated with CD8+ cytotoxic T cells. |
| Databáze: | OpenAIRE |
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