Browsing by Author "Rivera-Nieves, Jesus"

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    Ethnicity influences phenotype and clinical outcomes: Comparing a South American with a North American inflammatory bowel disease cohort
    (2022) Perez-Jeldres, Tamara; Pizarro, Benjamin; Ascui, Gabriel; Orellana, Matias; Cerda-Villablanca, Mauricio; Alvares, Danilo; de la Vega, Andres; Cannistra, Macarena; Cornejo, Barbara; Baez, Pablo; Silva, Veronica; Arriagada, Elizabeth; Rivera-Nieves, Jesus; Estela, Ricardo; Hernandez-Rocha, Cristian; alvarez-Lobos, Manuel; Tobar, Felipe
    Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn disease (CD), has emerged as a global disease with an increasing incidence in developing and newly industrialized regions such as South America. This global rise offers the opportunity to explore the differences and similarities in disease presentation and outcomes across different genetic backgrounds and geographic locations. Our study includes 265 IBD patients. We performed an exploratory analysis of the databases of Chilean and North American IBD patients to compare the clinical phenotypes between the cohorts. We employed an unsupervised machine-learning approach using principal component analysis, uniform manifold approximation, and projection, among others, for each disease. Finally, we predicted the cohort (North American vs Chilean) using a random forest. Several unsupervised machine learning methods have separated the 2 main groups, supporting the differences between North American and Chilean patients with each disease. The variables that explained the loadings of the clinical metadata on the principal components were related to the therapies and disease extension/location at diagnosis. Our random forest models were trained for cohort classification based on clinical characteristics, obtaining high accuracy (0.86 = UC; 0.79 = CD). Similarly, variables related to therapy and disease extension/location had a high Gini index. Similarly, univariate analysis showed a later CD age at diagnosis in Chilean IBD patients (37 vs 24; P = .005). Our study suggests a clinical difference between North American and Chilean IBD patients: later CD age at diagnosis with a predominantly less aggressive phenotype (39% vs 54% B1) and more limited disease, despite fewer biological therapies being used in Chile for both diseases.
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    Implementation of Mass Cytometry as a Tool for Mechanism of Action Studies in Inflammatory Bowel Disease
    (2018) Tyler, Christopher J.; Perez-Jeldres, Tamara; Ehinger, Erik; Capaldo, Brian; Karuppuchamy, Thangaraj; Boyer, Joshua D.; Patel, Derek; Dulai, Parambir; Boland, Brigid S.; Lannigan, Joanne; Eckmann, Lars; Ernst, Peter B.; Sandborn, William J.; Ho, Samuel B.; Rivera-Nieves, Jesus
    Background: Novel therapeutics for inflammatory bowel disease (IBD) are under development, yet mechanistic readouts at the tissue level are lacking. Techniques to assess intestinal immune composition could represent a valuable tool for mechanism of action (MOA) studies of novel drugs. Mass cytometry enables analysis of intestinal inflammatory cell infiltrate and corresponding molecular fingerprints with unprecedented resolution. Here, we aimed to optimize the methodology for isolation and cryopreservation of cells from intestinal tissue to allow for the potential implementation of mass cytometry in MOA studies.
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    Inherent Immune Cell Variation Within Colonic Segments Presents Challenges for Clinical Trial Design
    (2020) Tyler, Christopher J.; Guzman, Mauricio; Lundborg, Luke R.; Yeasmin, Shaila; Perez-Jeldres, Tamara; Yarur, Andres; Behm, Brian; Dulai, Parambir S.; Patel, Derek; Bamias, Giorgos; Rivera-Nieves, Jesus
    Background and Aims: Intestinal biopsy sampling during IBD trials represents a valuable adjunct strategy for understanding drug responses at the tissue level. Given the length and distinctive embryonic origins of the proximal and distal colon, we investigated whether inherent regional differences of immune cell composition could introduce confounders when sampling different disease stages, or pre/post drug administration. Here, we capitalise on novel mass cytometry technology to perform deep immunophenotyping of distinct healthy colonic segments, using the limited numbers of biopsies that can be harvested from patients.
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    Sphingosine-1-Phosphate Lyase Inhibition Alters the S1P Gradient and Ameliorates Crohn's-Like Ileitis by Suppressing Thymocyte Maturation
    (2020) Karuppuchamy, Thangaraj; Tyler, Christopher J.; Lundborg, Luke R.; Perez-Jeldres, Tamara; Kimball, Abigail K.; Clambey, Eric T.; Jedlicka, Paul; Rivera-Nieves, Jesus
    Background: Lymphocytes recirculate from tissues to blood following the sphingosine-1-phosphate (S1P) gradient (low in tissues, high in blood), maintained by synthetic and degradative enzymes, among which the S1P lyase (SPL) irreversibly degrades S1P. The role of SPL in the intestine, both during homeostasis and IBD, is poorly understood. We hypothesized that modulation of tissue S1P levels might be advantageous over S1P receptor (S1PR) agonists (eg, fingolimod, ozanimod, etrasimod), as without S1PR engagement there might be less likelihood of potential off-target effects.
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    Targeting Sphingosine-1-Phosphate Signaling in Immune-Mediated Diseases: Beyond Multiple Sclerosis
    (2021) Perez-Jeldres, Tamara; Alvarez-Lobos, Manuel; Rivera-Nieves, Jesus
    Sphingosine-1-phosphate (S1P) is a bioactive lipid metabolite that exerts its actions by engaging 5 G-protein-coupled receptors (S1PR1-S1PR5). S1P receptors are involved in several cellular and physiological events, including lymphocyte/hematopoietic cell trafficking. An S1P gradient (low in tissues, high in blood), maintained by synthetic and degradative enzymes, regulates lymphocyte trafficking. Because lymphocytes live long (which is critical for adaptive immunity) and recirculate thousands of times, the S1P-S1PR pathway is involved in the pathogenesis of immune-mediated diseases. The S1PR1 modulators lead to receptor internalization, subsequent ubiquitination, and proteasome degradation, which renders lymphocytes incapable of following the S1P gradient and prevents their access to inflammation sites. These drugs might also block lymphocyte egress from lymph nodes by inhibiting transendothelial migration. Targeting S1PRs as a therapeutic strategy was first employed for multiple sclerosis (MS), and four S1P modulators (fingolimod, siponimod, ozanimod, and ponesimod) are currently approved for its treatment. New S1PR modulators are under clinical development for MS, and their uses are being evaluated to treat other immune-mediated diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriasis. A clinical trial in patients with COVID-19 treated with ozanimod is ongoing. Ozanimod and etrasimod have shown promising results in IBD; while in phase 2 clinical trials, ponesimod has shown improvement in 77% of the patients with psoriasis. Cenerimod and amiselimod have been tested in SLE patients. Fingolimod, etrasimod, and IMMH001 have shown efficacy in RA preclinical studies. Concerns relating to S1PR modulators are leukopenia, anemia, transaminase elevation, macular edema, teratogenicity, pulmonary disorders, infections, and cardiovascular events. Furthermore, S1PR modulators exhibit different pharmacokinetics; a well-established first-dose event associated with S1PR modulators can be mitigated by gradual up-titration. In conclusion, S1P modulators represent a novel and promising therapeutic strategy for immune-mediated diseases.