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      Sphingosine-1-Phosphate Lyase Inhibition Alters the S1P Gradient and Ameliorates Crohn’s-Like Ileitis by Suppressing Thymocyte Maturation

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          Abstract

          Sphingosine-1-phosphate (S1P) receptor agonists are a promising therapeutic alternative to anti-integrin antibodies in inflammatory bowel disease. Here, we report that modulation of tissue S1P levels via inhibition of the S1P lyase might be an effective alternative, acting by interference with thymocyte maturation.

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          Most cited references50

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          Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1.

          Adaptive immunity depends on T-cell exit from the thymus and T and B cells travelling between secondary lymphoid organs to survey for antigens. After activation in lymphoid organs, T cells must again return to circulation to reach sites of infection; however, the mechanisms regulating lymphoid organ exit are unknown. An immunosuppressant drug, FTY720, inhibits lymphocyte emigration from lymphoid organs, and phosphorylated FTY720 binds and activates four of the five known sphingosine-1-phosphate (S1P) receptors. However, the role of S1P receptors in normal immune cell trafficking is unclear. Here we show that in mice whose haematopoietic cells lack a single S1P receptor (S1P1; also known as Edg1) there are no T cells in the periphery because mature T cells are unable to exit the thymus. Although B cells are present in peripheral lymphoid organs, they are severely deficient in blood and lymph. Adoptive cell transfer experiments establish an intrinsic requirement for S1P1 in T and B cells for lymphoid organ egress. Furthermore, S1P1-dependent chemotactic responsiveness is strongly upregulated in T-cell development before exit from the thymus, whereas S1P1 is downregulated during peripheral lymphocyte activation, and this is associated with retention in lymphoid organs. We find that FTY720 treatment downregulates S1P1, creating a temporary pharmacological S1P1-null state in lymphocytes, providing an explanation for the mechanism of FTY720-induced lymphocyte sequestration. These findings establish that S1P1 is essential for lymphocyte recirculation and that it regulates egress from both thymus and peripheral lymphoid organs.
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            Vedolizumab as induction and maintenance therapy for ulcerative colitis.

            Gut-selective blockade of lymphocyte trafficking by vedolizumab may constitute effective treatment for ulcerative colitis. We conducted two integrated randomized, double-blind, placebo-controlled trials of vedolizumab in patients with active disease. In the trial of induction therapy, 374 patients (cohort 1) received vedolizumab (at a dose of 300 mg) or placebo intravenously at weeks 0 and 2, and 521 patients (cohort 2) received open-label vedolizumab at weeks 0 and 2, with disease evaluation at week 6. In the trial of maintenance therapy, patients in either cohort who had a response to vedolizumab at week 6 were randomly assigned to continue receiving vedolizumab every 8 or 4 weeks or to switch to placebo for up to 52 weeks. A response was defined as a reduction in the Mayo Clinic score (range, 0 to 12, with higher scores indicating more active disease) of at least 3 points and a decrease of at least 30% from baseline, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1. Response rates at week 6 were 47.1% and 25.5% among patients in the vedolizumab group and placebo group, respectively (difference with adjustment for stratification factors, 21.7 percentage points; 95% confidence interval [CI], 11.6 to 31.7; P 1), as compared with 15.9% of patients who switched to placebo (adjusted difference, 26.1 percentage points for vedolizumab every 8 weeks vs. placebo [95% CI, 14.9 to 37.2; P<0.001] and 29.1 percentage points for vedolizumab every 4 weeks vs. placebo [95% CI, 17.9 to 40.4; P<0.001]). The frequency of adverse events was similar in the vedolizumab and placebo groups. Vedolizumab was more effective than placebo as induction and maintenance therapy for ulcerative colitis. (Funded by Millennium Pharmaceuticals; GEMINI 1 ClinicalTrials.gov number, NCT00783718.).
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              Single-cell mass cytometry of differential immune and drug responses across a human hematopoietic continuum.

              Flow cytometry is an essential tool for dissecting the functional complexity of hematopoiesis. We used single-cell "mass cytometry" to examine healthy human bone marrow, measuring 34 parameters simultaneously in single cells (binding of 31 antibodies, viability, DNA content, and relative cell size). The signaling behavior of cell subsets spanning a defined hematopoietic hierarchy was monitored with 18 simultaneous markers of functional signaling states perturbed by a set of ex vivo stimuli and inhibitors. The data set allowed for an algorithmically driven assembly of related cell types defined by surface antigen expression, providing a superimposable map of cell signaling responses in combination with drug inhibition. Visualized in this manner, the analysis revealed previously unappreciated instances of both precise signaling responses that were bounded within conventionally defined cell subsets and more continuous phosphorylation responses that crossed cell population boundaries in unexpected manners yet tracked closely with cellular phenotype. Collectively, such single-cell analyses provide system-wide views of immune signaling in healthy human hematopoiesis, against which drug action and disease can be compared for mechanistic studies and pharmacologic intervention.
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                Author and article information

                Journal
                Inflammatory Bowel Diseases
                Oxford University Press (OUP)
                1078-0998
                1536-4844
                February 2020
                January 06 2020
                December 06 2019
                February 2020
                January 06 2020
                December 06 2019
                : 26
                : 2
                : 216-228
                Affiliations
                [1 ]Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego, La Jolla, California, USA
                [2 ]Universidad Católica de Chile, Santiago, Chile
                [3 ]Hospital San Borja Arriarán, Santiago, Chile
                [4 ]Department of Anesthesiology Aurora, Colorado, USA
                [5 ]Department of Pathology, Aurora, Colorado, USA
                [6 ]Department of Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
                [7 ]Gastroenterology Section, San Diego VA Medical Center, La Jolla Village Drive, San Diego, California, USA
                Article
                10.1093/ibd/izz174
                6943703
                31807751
                d730abe0-2361-417c-9229-8579ecead3e2
                © 2019

                https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model

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