Jesús Rivera-Nieves

University of California, San Diego, San Diego, California, United States

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Publications (67)733.75 Total impact


  • No preview · Article · Mar 2016 · Inflammatory Bowel Diseases
  • Klaus Ley · Jesus Rivera-Nieves · William J Sandborn · Sanford Shattil
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    ABSTRACT: Integrins are activatable molecules that are involved in adhesion and signalling. Of the 24 known human integrins, 3 are currently targeted therapeutically by monoclonal antibodies, peptides or small molecules: drugs targeting the platelet αIIbβ3 integrin are used to prevent thrombotic complications after percutaneous coronary interventions, and compounds targeting the lymphocyte α4β1 and α4β7 integrins have indications in multiple sclerosis and inflammatory bowel disease. New antibodies and small molecules targeting β7 integrins (α4β7 and αEβ7 integrins) and their ligands are in clinical development for the treatment of inflammatory bowel diseases. Integrin-based therapeutics have shown clinically significant benefits in many patients, leading to continued medical interest in the further development of novel integrin inhibitors. Of note, almost all integrin antagonists in use or in late-stage clinical trials target either the ligand-binding site or the ligand itself.
    No preview · Article · Jan 2016 · Nature Reviews Drug Discovery
  • Jesús Rivera-Nieves
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    ABSTRACT: Purpose of review: We review the most recent developments regarding the targeting of molecules involved in the traffic of leukocytes for the treatment of inflammatory bowel diseases (IBD). Recent findings: We discuss the most important findings of one published phase II trial that targeted the β7 integrin (etrolizumab), two phase II trials that targeted the α4β7 integrin ligand: mucosal addressin cell adhesion molecule 1 (MAdCAM-1, PF-00547659), a phase II trial targeting the chemokine IP-10 (CXCL10) in Crohn's, and a phase II trial that targeted the sphingosine-1-phosphate receptor-1: ozanimod in patients with ulcerative colitis. Summary: Targeting molecules involved in leukocyte traffic has recently become an effective and well tolerated strategy for the treatment of IBD. Novel approaches now not only target the integrins on the lymphocyte surface, but also its endothelial ligand: MAdCAM-1. As with vedolizumab, antibodies against MAdCAM-1 appear most effective in ulcerative colitis rather than in Crohn's. Targeting chemokines or their receptors does not appear to have the same efficacy as those that target the most stable integrin: immunoglobulin superfamily interactions between the lymphocyte and endothelium. Preliminary results also suggest that the sphingosine-1-phosphate pathway might also be targeted therapeutically in IBD, no longer with parenterally administered antibodies but with orally administered small molecules.
    No preview · Article · Sep 2015 · Current opinion in gastroenterology

  • No preview · Article · Apr 2015 · Gastroenterology
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    ABSTRACT: The regulation of T cell and DC retention and lymphatic egress within and from the intestine is critical for intestinal immunosurveillance; however, the cellular processes that orchestrate this balance during IBD remain poorly defined. With the use of a mouse model of TNF-driven Crohn's-like ileitis (TNF(Δ) (ARE)), we examined the role of CCR7 in the control of intestinal T cell and DC retention/egress during experimental CD. We observed that the frequency of CCR7-expressing TH1/TH17 effector lymphocytes increased during active disease in TNF(Δ) (ARE) mice and that ΔARE/CCR7(-/-) mice developed exacerbated ileitis and multiorgan inflammation, with a marked polarization and ileal retention of TH1 effector CD4(+) T cells. Furthermore, adoptive transfer of ΔARE/CCR7(-/-) effector CD4(+) into lymphopenic hosts resulted in ileo-colitis, whereas those transferred with ΔARE/CCR7(+/+) CD4(+) T cells developed ileitis. ΔARE/CCR7(-/-) mice had an acellular draining MLN, decreased CD103(+) DC, and decreased expression of RALDH enzymes and of CD4(+)CD25(+)FoxP3(+) Tregs. Lastly, a mAb against CCR7 exacerbated ileitis in TNF(Δ) (ARE) mice, phenocopying the effects of congenital CCR7 deficiency. Our data underscore a critical role for the lymphoid chemokine receptor CCR7 in orchestrating immune cell traffic and TH1 versus TH17 bias during chronic murine ileitis. © Society for Leukocyte Biology.
    No preview · Article · Jan 2015 · Journal of Leukocyte Biology
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    ABSTRACT: The ability to measure the expression of proinflammatory cytokines from intestinal biopsies in patients with Crohn's disease in an accurate and reproducible way is critical for proof-of-concept and mechanism-of-action trials; however, the number of biopsies from a segment of the ileum or colon required to yield reproducible results has not been rigorously evaluated. We examined intestinal biopsies from patients with Crohn's disease to validate methods for detecting changes in inflammatory gene expression. To evaluate the reproducibility of gene expression measurements, intestinal biopsies were obtained from designated segments from 6 healthy controls, 6 patients with active Crohn's disease, and 6 patients with inactive Crohn's disease. Disease activity was based on the simple endoscopic score for Crohn's disease. Expression of 7 proinflammatory genes was measured from each biopsy using quantitative polymerase chain reaction. Using a linear mixed effects model, the power to detect transcriptional changes corresponding to active and inactive Crohn's disease was calculated. Total simple endoscopic score for Crohn's disease score corresponds with expression of most inflammatory biomarkers. For most genes, 2 to 5 biopsies are needed to reduce sampling error to <25% for most genes. To measure changes in mRNA expression corresponding to active versus inactive Crohn's disease, 1 to 2 intestinal biopsies from 3 patients before and after treatment are needed to yield power of at least 80%. Measuring proinflammatory gene expression from mucosal biopsies from patients with Crohn's disease is practicable and provides objective biomarkers that can be used in proof-of-concept and mechanism-of-action trials to assess response to therapy.
    No preview · Article · Dec 2014 · Inflammatory Bowel Diseases
  • Giorgos Bamias · Charles A. Dinarello · Jesús Rivera-Nieves

    No preview · Article · Nov 2014 · Gastroenterology
  • Brigid S Boland · Jesús Rivera-Nieves · Samir Gupta

    No preview · Article · May 2014 · Gastroenterology
  • Colm B Collins · Jesús Rivera-Nieves

    No preview · Article · Jan 2014 · Gastroenterology
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    Mahmoud H Mosli · Jesus Rivera-Nieves · Brian G Feagan
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    ABSTRACT: The medical management of idiopathic inflammatory bowel disease (IBD) has historically been based upon the use of broad-spectrum anti-inflammatory drugs such as corticosteroids and thiopurines. Recently, the identification of novel mechanisms central to the pathophysiology of IBD has provided more specific targets, including inhibition of leukocyte trafficking to the gut. In this article, we discuss the molecular biology of intestinal leukocyte trafficking and review the emerging therapies that target this process, including vedolizumab, natalizumab, etrolizumab, PF-547659, alicaforsen, efalizumab, and emerging members of this class.
    Preview · Article · Jan 2014 · Drugs
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    ABSTRACT: BACKGROUND: Pharmacological activation of the S1P1 receptor (S1P1R) results in, 1) disruption of lymphocyte egress from secondary lymphoid organs, and 2) therapeutic efficacy in preclinical models of inflammatory bowel disease (IBD). However, in addition to sequestration of lymphocytes within lymph nodes, other mechanisms of action may contribute to the anti-inflammatory effect of S1P1R agonists. Aim: The aim of this study was to begin to understand the regulation of the S1P metabolic pathway in patients with ulcerative colitis (UC) and mouse models of IBD and to assess the efficacy and mechanism of action of RPC1063, a potent S1P1R agonist, in the SAMP1YitFc mouse model of IBD.METHODS: Biopsies (n = 11) were collected from involved and uninvolved sites during routine endoscopy of patients with ulcerative colitis. Tissue was collected from SAMP1YitFc and non-inflamed AKR mice (n = 6-9) and RAG-/- mice adoptively transferred with CD4+CD45RBhi or CD4+CD45RBhi+lo cells (n = 3-4). S1P metabolic pathway enzymes were analyzed by RT-PCR. After the onset of ileitis RPC1063 (1.2 mg/kg/po/d), dexamethasone (4 mg/kg/po/d) or vehicle was administered for 14 days to SAMP1YitFc mice (n = 5-7). Ileitis severity was analyzed in a blinded manner by a pathologist, and tissue extracts analyzed for cytokine and chemokine protein expression.RESULTS: At inflamed sites, UC patient biopsies demonstrated decreased expression of S1P lyase (S1PL; 0.85 +/- 0.15-fold, P = 0.001) and increased sphingosine-1 kinase (SPHK1; 5.6 +/- 5.7-fold, P = 0.001). In agreement, ileum from SAMP1YitFc mice and colon from RAG-/- CD4+CD45RBhi adoptive transfer mice also show a decrease in S1PL (5.6-fold and 2.6-fold, P < 0.05) and increase in SPHK1 (1.8- and 1.9-fold, P < 0.05). Changes in expression levels correlated with disease severity in SAMP1YitFc mice. In agreement with prior studies in colitis models, a dose of RPC1063 that achieves a 68% reduction in circulating lymphocytes significantly suppressed chronic inflammation (2.1-fold, P < 0.05) and mucosal thickening (1.9-fold, P < 0.05) in the small intestine of SAMP1YitFc mice. A reduction in 18/22 elevated cytokines and chemokines was observed, with TNF[alpha], MCP-1, MIP-1[beta], MIP-2, LIF, IL-6, IL-12p40, and IL-13 reaching statistical significance.CONCLUSIONS: These results suggest that there is dysregulation of the S1P metabolic pathway that may result in elevated S1P at sites of inflammation within the intestine of patients with UC and in animal models of IBD. RPC1063 treatment restricted lymphocyte trafficking, blunted proinflammatory cytokine and chemokine expression and ameliorated histopathological features of IBD in SAMP1YitFc mice. RPC1063 is currently in clinical development for the treatment of patients with UC and multiple sclerosis.(C) Crohn's & Colitis Foundation of America, Inc.
    No preview · Article · Dec 2013 · Inflammatory Bowel Diseases
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    ABSTRACT: Fecal alpha-1-antitrypsin (AAT) clearance has been a marker of clinical disease severity in inflammatory bowel diseases (IBDs) for many years. Although AAT deficiency is more often associated with lung and liver pathologies, AAT-deficient patients with concomitant IBD have been shown to develop more aggressive disease and rapid progression to surgery. Although recent studies have highlighted the pleiotropic anti-inflammatory functions of AAT, including reducing proinflammatory cytokine production and suppressing immune cell activation, its potential therapeutic role in IBD has not been described. The therapeutic potential of human AAT administration was assessed in murine models of IBD including new-onset and established chemically induced colitis and spontaneous chronic murine ileitis. Histological assessment of inflammation, cytokine secretion profiling, and flow cytometric evaluation of inflammatory infiltrate were performed in each model. The effect of AAT on intestinal barrier function was also examined both in vitro and in vivo. AAT attenuated inflammation in small and large intestinal IBD models through reduced secretion of proinflammatory cytokines, inflammatory cell infiltration, and reduced tissue injury. AAT also increased intestinal restitution after chemically induced colitis. AAT significantly decreased intestinal permeability in vitro and in vivo as part of a protective mechanism for both acute and chronic models of IBD. Our findings describe a beneficial role for AAT in IBD models through suppression of cytokine production and enhanced intestinal barrier function. This raises the possibility that AAT supplementation, which has a long history of proven safety, may have a therapeutic effect in human IBD.
    Full-text · Article · Jul 2013 · Inflammatory Bowel Diseases

  • No preview · Article · May 2013 · Gastroenterology
  • Giorgos Bamias · David J Clark · Jesús Rivera-Nieves
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    ABSTRACT: Dysregulated recruitment of leukocytes into the intestine is a characteristic feature of IBD. Several families of molecules regulate the influx of these cells into sites of inflammation within the gastrointestinal tract. Pharmacological blockade of interactions between molecules that mediate the formation of stable bonds (integrins) and their endothelial ligands has already shown clinical efficacy. Antibodies that target participant molecules have been approved by the US Federal Drug Administration for use in Crohn's, multiple sclerosis (MS) (i.e. natalizumab) and psoriasis (i.e. efalizumab). A more recent additional family of drugs, which might also interfere with lymphocyte traffic (i.e. sphingosine-1-phosphate receptor agonists: fingolimod) is in clinical use for MS and just recently entered the clinical trial stage for ulcerative colitis. In the present review we discuss basic aspects of clinically relevant molecules and compile the clinical studies that support the targeting of specific steps of the leukocyte adhesion cascade for therapeutic purposes in IBD.
    No preview · Article · Apr 2013 · Current drug targets
  • Jesús Rivera-Nieves · María T Abreu

    No preview · Article · Mar 2013 · Gastroenterology
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    ABSTRACT: Background The earliest endoscopically-evident lesion in Crohn's disease is the aphthous ulcer, which develops over ectopic lymphoid tissues (ie, inducible lymphoid follicles (ILF), tertiary lymphoid tissue (TLT)) in the chronically inflamed intestine. ILF/TLT are induced within effector sites by homeostatic lymphoid chemokines, but their role in the development of intestinal ILF/TLT and in the pathogenesis of Crohn's disease is poorly understood. Design Using a mouse model of Crohn's-like ileitis (TNF∆ARE) which develops florid induction of ILF/TLT within its terminal ileum, the contribution of the CCR7/CCL19/CCL21 chemokine axis during the development of TLT and its role in disease pathogenesis were assessed. Results Both CCL19 and CCL21 were increased within the inflamed ileum of TNF∆ARE mice, which resulted in CCR7 internalisation and impaired T cell chemotaxis. ILF/TLT were a major source of CCL19 and CCL21 and increased local synthesis, augmented recruitment/retention of effector, naïve and central memory T cell subsets within the inflamed ileum. Immunoblockade of CCR7 resulted in further effector T cell retention and exacerbation of ileitis. Conclusions Induction of ILF/TLT in the chronically inflamed intestine alters the homeostatic CCL19-CCL21 lymphoid-chemokine gradient and increases recruitment/retention of effector CCR7+ T cell subsets within the terminal ileum, contributing to the perpetuation of chronic inflammation. Thus, blockade of CCR7 or its ligands might result in deleterious consequences for subjects with chronic inflammatory diseases.
    No preview · Article · Jan 2013 · Gut
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    ABSTRACT: Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract (GI) for which treatments with immunosuppressive drugs has significant side-effects. Consequently, there is an clinical need for site-specific and non-toxic delivery of therapeutic genes or drugs for CD and related disorders such as inflammatory bowel disease. The aim of this study was to validate an gene delivery platform based on ultrasound-activated lipid-shelled microbubbles (MB) targeted to inflamed mesenteric endothelium in the CD-like TNFΔARE mouse model. MB bearing luciferase plasmid were functionalized with antibodies to MAdCAM-1 (MB-M) or VCAM-1 (MB-V), biomarkers of gut endothelial cell inflammation and evaluated in an in vitro flow chamber assay with appropriate ligands to confirm targeting specificity. Following MB retro-orbital injection in TNFΔARE mice, the mean contrast intensity in the ileocecal region from accumulated MB-M and MB-V was 8.5-fold and 3.6-fold greater, respectively, compared to MB-C. Delivery of luciferase plasmid to the GI tract in TNFΔARE mice was achieved by insonating the endothelial cell-bound agents using a commercial sonoporator. Luciferease expression in the midgut was detected 48 hours laster by bioluminescence imaging and further confirmed by immunohistochemical staining. The liver, spleen, heart, and kidney had no detectable bioluminesence following insonation. Transfection of the microcirculation guided by a targeted, acoustically-activated platform such as a ultrasound contrast agent microbubble has the potential to be a minimally-invasive treatment strategy to ameliorate CD and other inflammatory conditions.
    Full-text · Article · Nov 2012 · Journal of Controlled Release
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    ABSTRACT: Ulcerative colitis is a chronic inflammatory disease of the colon; as many as 25% of patients with this disease require hospitalization. The goals of hospitalization are to assess disease severity, exclude infection, administer rapidly acting and highly effective medication regimens, and determine response. During hospitalization, patients should be given venous thromboembolism prophylaxis and monitored for the development of toxic megacolon. Patients who do not respond to intravenous corticosteroids should be considered for rescue therapy with infliximab or cyclosporine. Patients who are refractory to medical therapies or who develop toxic megacolon should be evaluated promptly for colectomy. Patients who do respond to medical therapies should be discharged on an appropriate maintenance regimen when they meet discharge criteria. We review practical evidence-based management principles and propose a day-by-day algorithm for managing patients hospitalized for ulcerative colitis.
    No preview · Article · Jul 2012 · Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association
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    Full-text · Article · Dec 2011 · Inflammatory Bowel Diseases
  • Eoin McNamee · Joanne Masterson · Paul Jedlicka · Jesus Rivera-Nieves

    No preview · Article · Dec 2011 · Inflammatory Bowel Diseases

Publication Stats

2k Citations
733.75 Total Impact Points

Institutions

  • 2011-2015
    • University of California, San Diego
      • Division of Gastroenterology
      San Diego, California, United States
  • 2012
    • VA San Diego Healthcare System
      San Diego, California, United States
  • 2008-2011
    • University of Colorado
      • • Division of General Internal Medicine
      • • Department of Medicine
      Denver, Colorado, United States
    • La Jolla Institute for Allergy & Immunology
      لا هویا, California, United States
  • 2000-2008
    • University of Virginia
      • Department of Pathology
      Charlottesville, Virginia, United States
  • 2006
    • Georg-August-Universität Göttingen
      Göttingen, Lower Saxony, Germany
  • 2001
    • Yakult Central Institute for Microbiological Research
      Musashino, Tōkyō, Japan
    • Cedars-Sinai Medical Center
      • Cedars Sinai Medical Center
      Los Ángeles, California, United States