599 research outputs found

    Human T-bet+ B cell development is associated with BTK activity and suppressed by evobrutinib

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    Recent clinical trials have shown promising results for the next-generation Bruton's tyrosine kinase (BTK) inhibitor evobrutinib in the treatment of multiple sclerosis (MS). BTK has a central role in signaling pathways that govern the development of B cells. Whether and how BTK activity shapes B cells as key drivers of MS is currently unclear. Compared with levels of BTK protein, we found higher levels of phospho-BTK in ex vivo blood memory B cells from patients with relapsingremitting MS and secondary progressive MS compared with controls. In these MS groups, BTK activity was induced to a lesser extent after anti-IgM stimulation. BTK positively correlated with CXCR3 expression, both of which were increased in blood B cells from clinical responders to natalizumab (anti-VLA-4 antibody) treatment. Under in vitro T follicular helper-like conditions, BTK phosphorylation was enhanced by T-bet-inducing stimuli, IFN-Îł and CpG-ODN, while the expression of T-bet and T-bet-associated molecules CXCR3, CD21, and CD11c was affected by evobrutinib. Furthermore, evobrutinib interfered with in vitro class switching, as well as memory recall responses, and disturbed CXCL10-mediated migration of CXCR3+ switched B cells through human brain endothelial monolayers. These findings demonstrate a functional link between BTK activity and disease-relevant B cells and offer valuable insights into how next-generation BTK inhibitors could modulate the clinical course of patients with MS

    Inhibition of Bruton’s tyrosine kinase interferes with pathogenic B-cell development in inflammatory CNS demyelinating disease

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    Anti-CD20-mediated B-cell depletion effectively reduces acute multiple sclerosis (MS) flares. Recent data shows that antibody-mediated extinction of B cells as a lasting immune suppression, harbors the risk of developing humoral deficiencies over time. Accordingly, more selective, durable and reversible B-cell-directed MS therapies are needed. We here tested inhibition of Bruton's tyrosine kinase (BTK), an enzyme centrally involved in B-cell receptor signaling, as the most promising approach in this direction. Using mouse models of MS, we determined that evobrutinib, the first BTK inhibiting molecule being developed, dose-dependently inhibited antigen-triggered activation and maturation of B cells as well as their release of pro-inflammatory cytokines. Most importantly, evobrutinib treatment functionally impaired the capacity of B cells to act as antigen-presenting cells for the development of encephalitogenic T cells, resulting in a significantly reduced disease severity in mice. In contrast to anti-CD20, BTK inhibition silenced this key property of B cells in MS without impairing their frequency or functional integrity. In conjunction with a recent phase II trial reporting that evobrutinib is safe and effective in MS, our mechanistic data highlight therapeutic BTK inhibition as a landmark towards selectively interfering with MS-driving B-cell properties

    a randomized double blind placebo controlled phase 1 study of multiple ascending doses of subcutaneous m1095 an anti interleukin 17a f nanobody in moderate to severe psoriasis

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    Background Interleukin 17 is involved in the pathogenesis of psoriasis, a chronic debilitating disease. Objectives To evaluate the safety/tolerability, immunogenicity, pharmacokinetics/pharmacodynamics, and efficacy of M1095, an anti–interleukin 17A/F nanobody, in moderate-to-severe plaque psoriasis. Methods This multicenter, double-blind, placebo-controlled dose escalation phase 1 study randomized 44 patients 4:1 to treatment with subcutaneous M1095 (30, 60, 120, or 240 mg) or placebo biweekly for 6 weeks, in 4 ascending dose cohorts. Results The most frequent treatment-emergent adverse events with M1095 were pruritus (n = 4) and headache (n = 3); 2 patients withdrew owing to adverse events (injection site reaction and elevated liver enzyme levels). The terminal half-life of M1095 was 11 to 12 days. The area under the curve/maximum concentration was dose proportional. Of 10 M1095-treated patients positive for antidrug antibodies, 5 showed treatment-emergent antidrug antibody responses. There was no effect on M1095 exposure. Marked decreases in psoriasis inflammatory markers were observed with M1095. By day 85, 100% and 56% of patients receiving M1095, 240 mg, achieved psoriasis area and severity index 90 and 100, respectively. Improvements in static Physician's Global Assessment and affected body surface area were also seen. Limitations Interpretation of efficacy data is limited by the small sample size. Conclusion Multiple subcutaneous doses of M1095 showed a favorable safety profile with dose-dependent improvements in psoriasis

    Supplementary Figure 1

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    Supplementary figure from Danka Svecova, Martin W. Lubell, Florence Casset-Semanaz, Harald Mackenzie, Roland Grenningloh, James G. Krueger 'A randomized, double-blind, placebo-controlled phase 1 study of multiple ascending doses of subcutaneous M1095, an anti interleukin-17A/F Nanobody®, in moderate-to-severe psoriasis' accepted for publication in the Journal of the American Academy of Dermatolog

    Supplementary Figure 1

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    Supplementary figures from Danka Svecova, Martin W. Lubell, Florence Casset-Semanaz, Harald Mackenzie, Roland Grenningloh, James G. Krueger 'A randomized, double-blind, placebo-controlled phase 1 study of multiple ascending doses of subcutaneous M1095, an anti interleukin-17A/F Nanobody®, in moderate-to-severe psoriasis' accepted for publication in the Journal of the American Academy of Dermatolog

    Flip the coin: IL-7 and IL-7R in health and disease

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    Copyright © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.The cytokine IL-7 and its receptor, IL-7R, are critical for T cell and, in the mouse, B cell development, as well as differentiation and survival of naive T cells, and generation and maintenance of memory T cells. They are also required for innate lymphoid cell (ILC) development and maintenance, and consequently for generation of lymphoid structures and barrier defense. Here we discuss the central role of IL-7 and IL-7R in the lymphoid system and highlight the impact of their deregulation, placing a particular emphasis on their 'dark side' as promoters of cancer development. We also explore therapeutic implications and opportunities associated with either positive or negative modulation of the IL-7-IL-7R signaling axis.J.T.B. is funded by the consolidator grant ERC CoG-648455 from the European Research Council, under the European Union’s Horizon 2020 research and innovation programme, and the FAPESP/20015/2014 and PTDC/MEC-HEM/31588/2017 grants from Fundação para a Ciência e a Tecnologia, Portugal; S.K.D. is funded by the intramural program of the US National Cancer Institute, National Institutes of Health, and the Children’s Cancer Foundation; B.S. is funded by the MRC (United Kingdom) under U117573801 and MR/P011225/1.info:eu-repo/semantics/publishedVersio

    Supplementary Figure 1

    No full text
    Supplementary figure from Danka Svecova, Martin W. Lubell, Florence Casset-Semanaz, Harald Mackenzie, Roland Grenningloh, James G. Krueger 'A randomized, double-blind, placebo-controlled phase 1 study of multiple ascending doses of subcutaneous M1095, an anti interleukin-17A/F Nanobody®, in moderate-to-severe psoriasis' accepted for publication in the Journal of the American Academy of Dermatolog
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