Jesús Rivera-Nieves

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

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Publications (62)661.91 Total impact

  • Gastroenterology 04/2015; 148(4):S-106-S-107. DOI:10.1016/S0016-5085(15)30367-X · 16.72 Impact Factor
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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.
    Journal of Leukocyte Biology 01/2015; 97(6). DOI:10.1189/jlb.3HI0614-303R · 4.29 Impact Factor
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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.
    Inflammatory Bowel Diseases 12/2014; 21(2). DOI:10.1097/MIB.0000000000000264 · 4.46 Impact Factor
  • Giorgos Bamias · Charles A. Dinarello · Jesús Rivera-Nieves
    Gastroenterology 11/2014; 148(1). DOI:10.1053/j.gastro.2014.11.013 · 16.72 Impact Factor
  • Brigid S Boland · Jesús Rivera-Nieves · Samir Gupta
    Gastroenterology 05/2014; 147(1). DOI:10.1053/j.gastro.2014.05.019 · 16.72 Impact Factor
  • Colm B Collins · Jesús Rivera-Nieves
    Gastroenterology 01/2014; 146(3). DOI:10.1053/j.gastro.2014.01.030 · 16.72 Impact Factor
  • 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.
    Drugs 01/2014; 74(3). DOI:10.1007/s40265-013-0176-2 · 4.34 Impact Factor
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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.
    Inflammatory Bowel Diseases 12/2013; 19:S19. DOI:10.1097/01.MIB.0000438587.88410.47 · 4.46 Impact Factor
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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.
    Inflammatory Bowel Diseases 07/2013; 19(9). DOI:10.1097/MIB.0b013e31829292aa · 4.46 Impact Factor
  • 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.
    Current drug targets 04/2013; 14(12). DOI:10.2174/13894501113149990158 · 3.02 Impact Factor
  • Jesús Rivera-Nieves · María T Abreu
    Gastroenterology 03/2013; 144(5). DOI:10.1053/j.gastro.2013.03.020 · 16.72 Impact Factor
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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.
    Gut 01/2013; 62(1-1):53-62. DOI:10.1136/gutjnl-2011-301272 · 14.66 Impact Factor
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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.
    Journal of Controlled Release 11/2012; 165(3). DOI:10.1016/j.jconrel.2012.10.021 · 7.71 Impact Factor
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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.
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 07/2012; 10(12). DOI:10.1016/j.cgh.2012.07.006 · 7.90 Impact Factor
  • Eoin McNamee · Joanne Masterson · Paul Jedlicka · Jesus Rivera-Nieves
    Inflammatory Bowel Diseases 12/2011; 17:S10. DOI:10.1097/00054725-201112002-00029 · 4.46 Impact Factor
  • Inflammatory Bowel Diseases 12/2011; 17:S10-S11. DOI:10.1097/00054725-201112002-00030 · 4.46 Impact Factor
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    ABSTRACT: BACKGROUND; Imprinting an effector or regulatory phenotype on naïve T cells requires education at induction sites by dendritic cells (DC). Objectives To analyse the effect of inflammation on the frequency of mononuclear phagocytes (MP) and the effect of altering their frequency by administration of Flt3-L in chronic ileitis. Using a tumour necrosis factor (TNF) driven model of ileitis (ie, TNFΔARE) that recapitulates many features of Crohn's disease (CD), dynamic changes in the frequency and functional state of MP within the inflamed ileum were assessed by flow cytometry, immunofluorescence and real-time reverse-transcription PCR and by generating CX(3)CR1 GFP-reporter TNFΔARE mice. The effect of Flt3-L supplementation on the severity of ileitis, and the frequency of CD103(+) DC and of FoxP3(+) regulatory T cells was also studied in TNFΔARE mice. CD11c(Hi)/MHCII(+) MP accumulated in inflamed ilea, predominantly mediated by expansion of the CX(3)CR1(+) MP subpopulation. This coincided with a decreased pro-regulatory CD103(+) DC. The phenotype of these MP was that of activated cells, as they expressed increased CD80 and CD86 on their surface. Flt3-ligand administration resulted in a preferential expansion of CD103(+) DC that attenuated the severity of ileitis in 20-week-old TNFΔARE mice, mediated by increased CD4(+)/CD25(+)/FoxP3(+) regulatory T cells. Results support a role for Flt3-L as a potential therapeutic agent in Crohn's-like ileitis.
    Gut 11/2011; 61(8):1154-62. DOI:10.1136/gutjnl-2011-300820 · 14.66 Impact Factor
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    ABSTRACT: Retinoic acid (RA), produced by intestinal epithelial cells (IECs) and dendritic cells (DCs) promotes the induction of regulatory T cells (Tregs) and decreases the induction of T-helper (Th)17 cells. We studied the roles of RA in mice that overproduce tumor necrosis factor (TNF) and develop chronic ileitis (TNF_ARE mice). We assessed the frequency and function of CD103+ DCs, Th17 cells, and Tregs by flow cytometry, and we measured expression of cytokines and retinaldehyde dehydrogenase (RALDH) enzymes in ileum samples, DCs, and IECs by real-time polymerase chain reaction. We quantified RA by electrochemical analysis and examined the effect of RA supplementation on TNF-induced ileitis using histologic, coculture, and suppression assays and flow cytometry. Numbers of CD103+ DCs decreased in the inflamed ilea of mice with chronic disease; RA synthetic machinery (RALDH1,2) was down-regulated. Nevertheless, the proportion of CD4+, CD25+, FoxP3+ Tregs increased, indicating an alternate source for RA. IECs responded to reduced levels of RA by up-regulating RALDH3 in vivo and in vitro. Net tissue levels of RA remained lower in TNF+ARE than wild-type mice, indicating that epithelial up-regulation of RALDH3 could not maintain adequate concentrations of RA, probably because of loss of IEC mass. RA supplementation significantly attenuated disease by increasing the number and function of CD103+ DCs and Tregs and reducing Th17 cells. Reduced levels of RA appear to induce IECs to up-regulate synthesis of RA. RA supplementation attenuates ileitis through its effects on CD103+ DCs, Tregs, and Th17 cells. RA supplementation might offer therapeutic benefit in Crohn's disease.
    Gastroenterology 11/2011; 141(5):1821-31. DOI:10.1053/j.gastro.2011.05.049 · 16.72 Impact Factor
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    ABSTRACT: Intestinal remodeling and stricture formation is a complication of inflammatory bowel disease (IBD) that often requires surgical intervention. Although eosinophils are associated with mucosal remodeling in other organs and are increased in IBD tissues, their role in IBD-associated remodeling is unclear. Histological and molecular features of ileitis and remodeling were assessed using immunohistochemical, histomorphometric, flow cytometric, and molecular analysis (real-time RT-PCR) techniques in a murine model of chronic eosinophilic ileitis. Collagen protein was assessed by Sircol assay. Using a spontaneous eosinophilic Crohn's-like mouse model SAMP1/SkuSlc, we demonstrate an association between ileitis progression and remodeling over the course of 40 weeks. Mucosal and submucosal eosinophilia increased over the time course and correlated with increased histological inflammatory indices. Ileitis and remodeling increased over the 40 weeks, as did expression of fibronectin. CCR3-specific antibody-mediated reduction of eosinophils resulted in significant decrease in goblet cell hyperplasia, muscularis propria hypertrophy, villus blunting, and expression of inflammatory and remodeling genes, including fibronectin. Cellularity of local mesenteric lymph nodes, including T- and B-lymphocytes, was also significantly reduced. Thus, eosinophils participate in intestinal remodeling, supporting eosinophils as a novel therapeutic target.
    American Journal Of Pathology 09/2011; 179(5):2302-14. DOI:10.1016/j.ajpath.2011.07.039 · 4.59 Impact Factor
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    ABSTRACT: IL-37, a newly described member of the IL-1 family, functions as a fundamental inhibitor of innate inflammation and immunity. In the present study, we examined a role for IL-37 during experimental colitis. A transgenic mouse strain was generated to express human IL-37 (hIL-37tg), and these mice were subjected to dextran sulfate sodium (DSS)-induced colitis. Despite the presence of a CMV promoter to drive expression of IL-37, mRNA transcripts were not present in colons at the resting state. Expression was observed only upon disruption of the epithelial barrier, with a six- to sevenfold increase (P = 0.02) on days 3 and 5 after continuous exposure to DSS. During the development of colitis, clinical disease scores were reduced by 50% (P < 0.001), and histological indices of colitis were one-third less in hIL-37tg mice compared with WT counterparts (P < 0.001). Reduced inflammation was associated with decreased leukocyte recruitment into the colonic lamina propria. In addition, release of IL-1β and TNFα from ex vivo colonic explant tissue was decreased 5- and 13-fold, respectively, compared with WT (P ≤ 0.005), whereas IL-10 was increased sixfold (P < 0.001). However, IL-10 was not required for the anti-inflammatory effects of IL-37 because IL-10-receptor antibody blockade did not reverse IL-37-mediated protection. Mechanistically, IL-37 originating from hematopoietic cells was sufficient to exert anti-inflammatory effects because WT mice reconstituted with hIL-37tg bone marrow were protected from colitis. Thus, IL-37 emerges as key modulator of intestinal inflammation.
    Proceedings of the National Academy of Sciences 08/2011; 108(40):16711-6. DOI:10.1073/pnas.1111982108 · 9.67 Impact Factor

Publication Stats

2k Citations
661.91 Total Impact Points


  • 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
  • 2009–2011
    • University of Colorado
      • Department of Medicine
      Denver, Colorado, United States
  • 2008
    • La Jolla Institute for Allergy & Immunology
      لا هویا, California, United States
  • 2000–2007
    • 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