Ustekinumab Inhibits T Follicular Helper Cell Differentiation in Patients With Crohn’s Disease

Globig, Anna-Maria; Sommer, N.; Wild, Katharina; Schardey, Josefine; Zoldan, Katharina; Thomann, A; Schulte, Lucas-Alexander; Schreiner, Rupert; Reindl, Wolfgang; Klaus, Jochen; Schempp, Christoph M.; Hofmann, Maike; Thimme, Robert; Böettler, Tobias; Hasselblatt, Peter

doi:10.1016/j.jcmgh.2020.07.005

Cited by 21 publications

(13 citation statements)

References 41 publications

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“…Recently, pathogenicity of minor subsets of T helper cells is being focused on. The Th1/Th17 double positive T-cell and T follicular helper cell were candidate of the pathogenesis of CD [17,21]. We also evaluated Th1/Th17 double-positive T cells, the population was however very low and could not find definitive results.…”

Section: Discussionmentioning

confidence: 99%

“…We also evaluated Th1/Th17 double-positive T cells, the population was however very low and could not find definitive results. UST were reported to inhibit T follicular helper cell differentiation in patients with CD [21]. The therapeutic effect of UST may include suppression of these inflammatory T-cell subsets as well as suppression of Th 17 cells.…”

Section: Discussionmentioning

confidence: 99%

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Ustekinumab Improves Active Crohn’s Disease by Suppressing the T Helper 17 Pathway

et al. 2021

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Background: Ustekinumab (UST), an antibody targeting the p40 subunit of interleukin (IL)-12 and IL-23, is effective in treating Crohn’s disease (CD). To clarify the mechanism of UST, we investigated T-cell differentiation in CD patients treated with UST. Methods: Twenty-seven patients with active CD were enrolled in this study. Seventeen patients were treated with UST, and 10 patients were treated with anti-tumor necrosis factor (TNF)-alpha therapy. The changes in the proportions of T-cell subsets after these therapies were analyzed by flow cytometry. Comprehensive gene expression changes in the colonic mucosa were also evaluated. Results: The frequency of T helper (Th) 17 cells was significantly decreased in the peripheral blood of patients with active CD after UST therapy. Anti-TNF therapy had a minimal effect on Th17 cells but increased the proportion of regulatory T cells. Enrichment analysis showed the expression of genes involved in the Th17 differentiation pathway was downregulated in the colonic mucosa after UST but not anti-TNF therapy. There were no common differentially expressed genes between CD patients treated with UST and anti-TNF therapy, suggesting a clear difference in their mechanism of action. Conclusion: In patients with active CD, UST therapy suppressed Th17 cell differentiation both in the peripheral blood and colonic tissues.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ustekinumab Improves Active Crohn’s Disease by Suppressing the T Helper 17 Pathway

et al. 2021

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“…Furthermore, others antigen presenting cells (APCs) and in particular SlanMo, a subset of non-classical monocytes known to be a major source of IL-12 and IL-23 was impaired in several autoimmune diseases [ 80 ]. A recent study using the Mab ustekinumab directed against the shared p40 subunit of IL-12 and IL-23 in crohn’s disease patients showed that this treatment leads to a decrease in Tfh cell differentiation in vitro [ 81 ]. Unfortunately, limited data are currently available on the interaction between APCs and Tfh cells in the context of SSc.…”

Section: Targeting Tfh In Systemic Sclerosis: Perspectives From Other Auto-immune Diseases and Gvhd Modelsmentioning

confidence: 99%

TFH cells in systemic sclerosis

et al. 2021

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Systemic sclerosis is an autoimmune disease characterized by excessive dermal fibrosis with progression to internal organs, vascular impairment and immune dysregulation evidenced by the infiltration of inflammatory cells in affected tissues and the production of auto antibodies. While the pathogenesis remains unclear, several data highlight that T and B cells deregulation is implicated in the disease pathogenesis. Over the last decade, aberrant responses of circulating T follicular helper cells, a subset of CD4 T cells which are able to localise predominantly in the B cell follicles through a high level of chemokine receptor CXCR5 expression are described in pathogenesis of several autoimmune diseases and chronic graft-versus-host-disease. In the present review, we summarized the observed alteration of number and frequency of circulating T follicular helper cells in systemic sclerosis. We described their role in aberrant B cell activation and differentiation though interleukine-21 secretion. We also clarified T follicular helper-like cells involvement in fibrogenesis in both human and mouse model. Finally, because T follicular helper cells are involved in both fibrosis and autoimmune abnormalities in systemic sclerosis patients, we presented the different strategies could be used to target T follicular helper cells in systemic sclerosis, the therapeutic trials currently being carried out and the future perspectives from other auto-immune diseases and graft-versus-host-disease models.

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“…CD patients with clinical response to ustekinumab (IL-12 and IL-23 antagonists) had reduced frequencies of circulating Tfh cells in a concentration-dependent manner. Ustekinumab inhibited Tfh cell differentiation in vitro , and ustekinumab therapy can reduce the germinal center activity in CD patients in vivo [ 83 ].…”

Section: The Role Of Tfh Cells and Il-21 In Ibdmentioning

confidence: 99%

The Role of T Follicular Helper Cells and Interleukin-21 in the Pathogenesis of Inflammatory Bowel Disease

Sun

Kong

et al. 2021

Gastroenterology Research and Practice

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T follicular helper (Tfh) cells represent a novel subset of CD4+ T cells which can provide critical help for germinal center (GC) formation and antibody production. The Tfh cells are characterized by the expression of CXC chemokine receptor 5 (CXCR5), programmed death 1 (PD-1), inducible costimulatory molecule (ICOS), B cell lymphoma 6 (BCL-6), and the secretion of interleukin-21 (IL-21). Given the important role of Tfh cells in B cell activation and high-affinity antibody production, Tfh cells are involved in the pathogenesis of many human diseases. Inflammatory bowel disease (IBD) is a group of chronic inflammatory diseases characterized by symptoms such as diarrhea, abdominal pain, and weight loss. Ulcerative colitis (UC) and Crohn’s disease (CD) are the most studied types of IBD. Dysregulated mucosal immune response plays an important role in the pathogenesis of IBD. In recent years, many studies have identified the critical role of Tfh cells and IL-21 in the pathogenic process IBD. In this paper, we will discuss the role of Tfh cells and IL-21 in IBD pathogenesis.

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Ustekinumab Inhibits T Follicular Helper Cell Differentiation in Patients With Crohn’s Disease

Cited by 21 publications

References 41 publications

Ustekinumab Improves Active Crohn’s Disease by Suppressing the T Helper 17 Pathway

Ustekinumab Improves Active Crohn’s Disease by Suppressing the T Helper 17 Pathway

TFH cells in systemic sclerosis

The Role of T Follicular Helper Cells and Interleukin-21 in the Pathogenesis of Inflammatory Bowel Disease

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