scholarly journals Effects of Immunomodulatory Drug Fingolimod (FTY720) on Chlamydia Dissemination and Pathogenesis

2020 ◽  
Vol 88 (11) ◽  
Author(s):  
Zengzi Zhou ◽  
Lingxiang Xie ◽  
Luying Wang ◽  
Min Xue ◽  
Dabao Xu ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Gastrointestinal Tract ◽  
Genital Tract ◽  
Immune Cell ◽  
Cell Trafficking ◽  
Rectal Swabs ◽  
Sphingosine 1 Phosphate ◽  
Immunomodulatory Drug ◽  
Live Organism

ABSTRACT Fingolimod (FTY720), an FDA-approved immunomodulatory drug for treating multiple sclerosis, is an agonist of sphingosine-1-phosphate receptor (S1PR), which has been used as a research tool for inhibiting immune cell trafficking. FTY720 was recently reported to inhibit Chlamydia dissemination. Since genital Chlamydia spreading to the gastrointestinal tract correlated with its pathogenicity in the upper genital tract, we evaluated the effect of FTY720 on chlamydial pathogenicity in the current study. Following an intravaginal inoculation, live chlamydial organisms were detected in mouse rectal swabs. FTY720 treatment significantly delayed live organism shedding in the rectal swabs. However, FTY720 failed to block chlamydial spreading to the gastrointestinal tract. The live chlamydial organisms recovered from rectal swabs reached similar levels between mice with or without FTY720 treatment by day 42 in C57BL/6J and day 28 in CBA/J mice, respectively. Thus, genital Chlamydia is able to launch a 2nd wave of spreading via an FTY720-resistant pathway after the 1st wave of spreading is inhibited by FTY720. As a result, all mice developed significant hydrosalpinx. The FTY720-resistant spreading led to stable colonization of chlamydial organisms in the colon. Consistently, FTY720 did not alter the colonization of intracolonically inoculated Chlamydia. Thus, we have demonstrated that, following a delay in chlamydial spreading caused by FTY720, genital Chlamydia is able to both spread to the gastrointestinal tract via an FTY720-resistant pathway and maintain its pathogenicity in the upper genital tract. Further characterization of the FTY720-resistant pathway(s) explored by Chlamydia for spreading to the gastrointestinal tract may promote our understanding of Chlamydia pathogenic mechanisms.

Phase II trial of opaganib in patients with metastatic castration-resistant prostate cancer progressing on abiraterone or enzalutamide (NCT04207255).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. TPS191-TPS191
Author(s):  
Omer Kucuk ◽  
Charles Smith ◽  
Terry Plasse ◽  
Besim Ogretmen ◽  
Shikhar Mehrotra ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Immune Modulation ◽  
Immune Cell ◽  
Progression Free Survival ◽  
Competitive Inhibitor ◽  
Cell Trafficking ◽  
Castration Resistant Prostate Cancer ◽  
Free Survival ◽  
Castration Resistant ◽  
Sphingosine 1 Phosphate

TPS191 Background: Opaganib (Yeliva, ABC294640) is a first-in-class, sphingosine kinase-2 (SK2) selective inhibitor, with anticancer, anti-inflammatory and anti-viral activities. SK2, a lipid kinase catalyzes formation of the lipid signaling molecule sphingosine 1-phosphate (S1P). S1P promotes cancer growth, and proliferation and pathological inflammation, including inflammatory cytokine production. Specifically, by inhibiting the SK2 enzyme, opaganib blocks the synthesis of S1P which regulates fundamental biological processes such as cell proliferation, migration, immune cell trafficking and angiogenesis, and are also involved in immune-modulation and suppression of innate immune responses from T cells. Opaganib is a sphingosine-competitive inhibitor of SK2 and also inhibits dihydroceramide desaturase. Opaganib has antitumor activity against human and murine prostate cancer cell lines, and in xenograft (LNCaP) and syngeneic (MycCAP, TRAMP-C1) murine tumor models. In addition to its target effect of reducing sphingosine-1-phosphate, opaganib reduces both MYC and AR proteins through its kinase-blocking and desaturase-inhibiting properties, respectively. Methods: The study is open to patients with mCRPC who have been treated with at least one newer androgen antagonist (abiraterone or enzalutamide) and no prior chemotherapy for castration-resistant disease. Patients who are failing either abiraterone or enzalutamide may enroll, with the addition of opaganib. The trial design includes brief safety lead-in cohort 1a (abiraterone + opaganib 250 mg Q 12hr, 3/3 enrolled) and 1b (enzalutamide + opaganib 250 mg Q 12hr, 3/3 enrolled). These cohorts have been completed without any DLTs. We are now enrolling cohort 2 (abiraterone + opaganib 500 mg Q 12hr, 0/27 enrolled) and cohort 3 (enzalutamide + opaganib 500 mg Q 12hr, 8/27 enrolled). A total of 60 patients will be enrolled and response will be evaluated after 4 cycles (28 days/cycle) using a composite metric based on PSA, bone scan and RECIST measurements per PCWG3 criteria. Safety and tolerability will be monitored, and dose modifications will be allowed. Primary endpoint is disease control (stable disease or better) after 4 cycles. Secondary endpoints include overall survival, radiographic progression-free survival and PSA progression-free survival. Correlative studies include assessment of quality of life (QOL), circulating MDSCs, immune cells and clones with amplified AR or MYC. Supported by NIH grant P01 CA203628. Clinical trial information: NCT04207255.

Deep characterization of paired chromatin and transcriptomes in four immune cell types from multiple sclerosis patients

Epigenomics ◽  
2021 ◽  
Author(s):  
Sunjay Jude Fernandes ◽  
Matilda Ericsson ◽  
Mohsen Khademi ◽  
Maja Jagodic ◽  
Tomas Olsson ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Immune Cell ◽  
Cell Types ◽  
Chromatin Accessibility ◽  
Primary Role ◽  
Nucleotide Polymorphisms ◽  
Multiple Sclerosis Patients ◽  
Accessible Chromatin

Background: The putative involvement of chromatin states in multiple sclerosis (MS) is thus far unclear. Here we determined the association of chromatin-accessibility with concurrent genetic, epigenetic and transcriptional events. Material & methods: We generated paired assay for transposase-accessible chromatin sequencing and RNA-seq profiles from sorted blood immune CD4+ and CD8+ T cells, CD14+ monocytes and CD19+ B cells from healthy controls (HCs) and MS patients. Results: We identified differentially accessible regions between MS and HCs, primarily in CD4+ and CD19+. CD4+ regions were enriched for MS-associated single nucleotide polymorphisms and differentially methylated loci. In the vicinity of differentially accessible regions of CD4+ cells, 42 differentially expressed genes were identified. The top two dysregulated genes identified in this multilayer analysis were CCDC114 and SERTAD1. Conclusion: These findings provide new insight into the primary role of CD4+ and CD19+ cells in MS.

scholarly journals Clinical and epidemiological profile of patients diagnosed with multiple sclerosis in João Pessoa, Paraíba, Brazil

2015 ◽  
Vol 73 (9) ◽  
pp. 741-745 ◽  
Author(s):  
André Augusto Lemos Vidal de Negreiros ◽  
Rilva Lopes de Sousa-Munõz ◽  
Bianca Etelvina Santos de Oliveira ◽  
Paulo Virgolino da Nóbrega ◽  
Laíse Leilane Dias Monteiro
Keyword(s):  
Multiple Sclerosis ◽  
White People ◽  
Disability Status ◽  
Relapsing Remitting ◽  
Immunomodulatory Drug ◽  
Genetic And Environmental Factors ◽  
Epidemiological Profile ◽  
Epidemiological Characteristics ◽  
Brazilian Studies

Prevalence rates of multiple sclerosis (MS) suggest an interrelationship between genetic and environmental factors, ranging worldwide.Objectives Clinical and epidemiological characterization of MS patients in João Pessoa, Paraíba city.Methods Study involving patients treated in five services in the city.Results It included 87 patients with MS, representing a prevalence of 12.0 cases/100,000 population, mainly women (77%) and white people (66.7%) with mean age of 43 years and average age of the first outbreak of 32.2 years. Motor symptoms (65.5%) and relapsing-remitting clinical form (78.2%) predominated; the average of the Expanded Disability Status Scale (EDSS) scores was 3.5 and 72% used a type of immunomodulatory drug. There was a positive correlation between the number of outbreaks and the duration of the disease with EDSS scores.Conclusions The prevalence of the disease is considered average. The clinical and epidemiological characteristics are in line with most similar Brazilian studies.

scholarly journals Molecular characterization of perivascular drainage pathways in the murine brain

2017 ◽  
Vol 38 (4) ◽  
pp. 669-686 ◽  
Author(s):  
Melanie-Jane Hannocks ◽  
Michelle E Pizzo ◽  
Jula Huppert ◽  
Tushar Deshpande ◽  
N Joan Abbott ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Fluid Flow ◽  
Molecular Characterization ◽  
Immune Cell ◽  
Smooth Muscle Actin ◽  
Cell Trafficking ◽  
Cellular Markers ◽  
Waste Transfer ◽  
The Brain

Perivascular compartments surrounding central nervous system (CNS) vessels have been proposed to serve key roles in facilitating cerebrospinal fluid flow into the brain, CNS waste transfer, and immune cell trafficking. Traditionally, these compartments were identified by electron microscopy with limited molecular characterization. Using cellular markers and knowledge on cellular sources of basement membrane laminins, we here describe molecularly distinct compartments surrounding different vessel types and provide a comprehensive characterization of the arachnoid and pial compartments and their connection to CNS vessels and perivascular pathways. We show that differential expression of plectin, E-cadherin and laminins α1, α2, and α5 distinguishes pial and arachnoid layers at the brain surface, while endothelial and smooth muscle laminins α4 and α5 and smooth muscle actin differentiate between arterioles and venules. Tracer studies reveal that interconnected perivascular compartments exist from arterioles through to veins, potentially providing a route for fluid flow as well as the transport of large and small molecules.

scholarly journals Subcellular distribution of FTY720 and FTY720-phosphate in immune cells – another aspect of Fingolimod action relevant for therapeutic application

2015 ◽  
Vol 396 (6-7) ◽  
pp. 795-802 ◽  
Author(s):  
Matthias Schröder ◽  
Olga Arlt ◽  
Helmut Schmidt ◽  
Andrea Huwiler ◽  
Carlo Angioni ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Immune Cells ◽  
Subcellular Distribution ◽  
Immune Cell ◽  
Lipid Mediator ◽  
Sphingosine Kinase 2 ◽  
Relapsing Remitting ◽  
Sphingosine 1 Phosphate ◽  
Original Cell ◽  
Relapsing Remitting Multiple Sclerosis

Abstract FTY720 (Fingolimod; Gilenya®) is an immune-modulatory prodrug which, after intracellular phosphorylation by sphingosine kinase 2 (SphK2) and export, mimics effects of the endogenous lipid mediator sphingosine-1-phosphate. Fingolimod has been introduced to treat relapsing-remitting multiple sclerosis. However, little has been published about the immune cell membrane penetration and subcellular distribution of FTY720 and FTY720-P. Thus, we applied a newly established LC-MS/MS method to analyze the subcellular distribution of FTY720 and FTY720-P in subcellular compartments of spleen cells of wild type, SphK1- and SphK2-deficient mice. These studies demonstrated that, when normalized to the original cell volume and calculated on molar basis, FTY720 and FTY720-P dramatically accumulated several hundredfold within immune cells reaching micromolar concentrations. The amount and distribution of FTY720 was differentially affected by SphK1- and SphK2-deficiency. On the background of recently described relevant intracellular FTY720 effects in the nanomolar range and the prolonged application in multiple sclerosis, this data showing a substantial intracellular accumulation of FTY720, has to be considered for benefit/risk ratio estimates.

scholarly journals Anti-Integrin Therapy for Multiple Sclerosis

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Eiji Kawamoto ◽  
Susumu Nakahashi ◽  
Takayuki Okamoto ◽  
Hiroshi Imai ◽  
Motomu Shimaoka
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Cell Adhesion ◽  
Immune Cells ◽  
Cell Adhesion Molecules ◽  
Immune Cell ◽  
Critical Role ◽  
Cell Trafficking ◽  
Organ Specific ◽  
Integrin Alpha4

Integrins are the foremost family of cell adhesion molecules that regulate immune cell trafficking in health and diseases. Integrin alpha4 mediates organ-specific migration of immune cells to the inflamed brain, thereby playing the critical role in the pathogenesis of multiple sclerosis. Anti-alpha4 integrin therapy aiming to block infiltration of autoreactive lymphocytes to the inflamed brain has been validated in several clinical trials for the treatment of multiple sclerosis. This paper provides readers with an overview of the molecular and structural bases of integrin activation as well as rationale for using anti-alpha4 integrin therapy for multiple sclerosis and then chronicles the rise and fall of this treatment strategy using natalizumab, a humanized anti-alpha4 integrin.

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