Browsing by Subject "IBD"

Now showing 1 - 5 of 5
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    Altered STAT4 isoform expression in patients with inflammatory bowel disease.
    (Wolters Kluwer, 2015-10) Jabeen, Rukhsana; Miller, Lucy; Yao, Weiguo; Gupta, Sandeep; Steiner, Steven; Kaplan, Mark H.; Department of Pediatrics, IU School of Medicine
    BACKGROUND & AIMS: Crohn’s disease (CD) and ulcerative colitis (UC) are major forms of inflammatory bowel disease (IBD) and pathogenesis involves a complex interplay between genetic, environmental and immunological factors. We evaluated isoform expression of the IL-12-activated transcription factor STAT4 in children with CD and UC. METHODS: We performed a study where we collected biopsy samples from both newly diagnosed CD and UC patients. We further collected blood samples from newly diagnosed CD and UC patients as well as patients who had a flare-up after being in clinical remission, and examined the ratios of STAT4β/STAT4α mRNA. In addition to STAT4 isoforms we measured the expression of the cytokines TNFα, IFNγ, GM-CSF and IL-17 using PCR of biopsy samples and multiplex analysis of patient serum samples. RESULTS: Ratios of STAT4β/STAT4α were increased in specific GI tract segments in both CD and UC patients that correlate with location and severity of inflammation. In contrast, we did not observe changes in STAT4β/STAT4α ratios in biopsy specimens from eosinophilic esophagitis patients. We also observed increased STAT4β/STAT4α ratios in the peripheral blood mononuclear cells of UC and CD patients, compared to healthy controls. Ratios were normalized after patient treatment with steroids. CONCLUSIONS: Collectively, these data indicate that STAT4 isoforms could be an important non-invasive biomarker in the diagnosis and treatment of IBD, and that expression of these isoforms might provide further insight into the pathogenesis of IBD.
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    AMP peptide targets tight junctions to protect and heal barrier structure and function in models of IBD.
    (Wolters Kluwer, 2015-10) Chen, Peili; Bakke, Danika; Kolodziej, Lauren; Lodolce, James; Weber, Christopher R.; Boone, David L.; Toback, F. Gary; Department of Microbiology and Immunology, IU School of Medicine
    Background: A peptide derived from Antrum Mucosal Protein (AMP)-18 (gastrokine-1) reduces the extent of mucosal erosions and clinical severity in mice with dextran sulfate sodium (DSS)-induced colonic injury. The present study set out to determine if AMP peptide was also therapeutic for immune- and cytokine-mediated mouse models of intestinal injury and inflammatory bowel diseases (IBD) by enhancing and stabilizing tight junctions (TJs). Methods: Therapeutic effects of AMP peptide were examined in interleukin-10 deficient and a T cell adoptive transfer models of colitis in immunodeficient recombinase activating gene-1 knock-out (RAG-1−/−) mice. Mechanisms by which AMP peptide enhances barrier function and structure were studied ex vivo using intestine and colon from mice given lipopolysaccharide (LPS), and in AMP-18 deficient mice given DSS. Results: In interleukin-10 deficient mice given piroxicam, AMP peptide enhanced recovery after weight loss, protected against colon shortening and segmental dilation, and reduced the colitis activity score. In the T cell transfer model, treatment with the peptide protected against colon shortening. In mice given LPS in vivo to induce gut injury, AMP peptide prevented the onset of, and reversed established intestinal hyperpermeability by targeting TJ proteins and perijunctional actin.
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    Efficacy and Safety of Mirikizumab in a Randomized Phase 2 Study of Patients With Crohn’s Disease
    (Elsevier, 2022-02) Sands, Bruce E.; Peyrin-Biroulet, Laurent; Kierkus, Jaroslaw; Higgins, Peter D.R.; Fischer, Monika; Jairath, Vipul; Hirai, Fumihito; D’Haens, Geert; Belin, Ruth M.; Miller, Debra; Gomez-Valderas, Elisa; Naegeli, April N.; Tuttle, Jay L.; Pollack, Paul F.; Sandborn, William J.; Medicine, School of Medicine
    Background Mirikizumab is a humanized monoclonal antibody targeting interleukin 23p19 with demonstrated efficacy in psoriasis and ulcerative colitis. We investigated the safety and efficacy of mirikizumab in patients with moderate-to-severe Crohn’s disease (CD). Methods Patients (N = 191) were randomized (2:1:1:2) to receive placebo (PBO), 200, 600, or 1000 mg mirikizumab, administered intravenously (IV) every 4 weeks. Patients who received mirikizumab and achieved ≥1 point improvement in Simple Endoscopic Score-CD at Week 12 (rerandomized maintenance cohort) were rerandomized to continue their induction IV treatment (combined IV groups [IV-C]) or receive 300 mg mirikizumab subcutaneously (SC) every 4 weeks. Nonrandomized maintenance cohort included endoscopic nonimprovers (1000 mg) and PBO patients (PBO/1000 mg) who received 1000 mg mirikizumab IV from Week 12. The primary objective was to evaluate superiority of mirikizumab to PBO in inducing endoscopic response (50% reduction from baseline in Simple Endoscopic Score-CD) at Week 12. Results At Week 12, endoscopic response was significantly higher by the predefined 2-sided significance level of 0.1 for all mirikizumab groups compared with PBO (200 mg: 25.8%, 8/31, 95% confidence interval [CI], 10.4–41.2, P = .079; 600 mg: 37.5%, 12/32, 95% CI, 20.7–54.3, P = .003; 1000 mg: 43.8%, 28/64, 95% CI, 31.6–55.9, P < .001; PBO: 10.9 %, 7/64, 95% CI, 3.3–18.6). Endoscopic response at Week 52 was 58.5% (24/41) and 58.7% (27/46) in the IV-C and SC groups, respectively. Frequencies of adverse events (AE) in the mirikizumab groups were similar to PBO. Through Week 52, frequencies of treatment-emergent AEs were similar across all groups. Frequencies of serious AE and discontinuations due to AE were higher in the nonrandomized maintenance cohort. Conclusion Mirikizumab effectively induced endoscopic response after 12 weeks in patients with moderate-to-severe CD and demonstrated durable efficacy to Week 52. A detailed summary can be found in the Video Abstract. ClinicalTrials.gov, Number: NCT02891226
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    IBD Camp Oasis: A look at Participants’ Social-Emotional Well-Being and Protective Factors During Camp and Beyond
    (Oxford University Press, 2023-08-24) Singh, Namita; Steiner, Steven J.; Fauth, Rebecca; Moosmann, Danyel; Arnold, Janis; Elkadri, Abdul; Marinoni, Daniel; Molloy, Laurel; Johnson Rescola, Becky; Tung, Jeanne; Utterson, Elizabeth C.; Pediatrics, School of Medicine
    Background: Camp Oasis is an annual week-long camp serving children with inflammatory bowel disease (IBD) and hosted by the Crohn's and Colitis Foundation. Youth with IBD are at increased risk for mental health challenges, with Camp Oasis potentially mitigating these risks. The aim of this study is to measure change in and predictors of social-emotional well-being and protective factors of self-worth as a result of attending Camp Oasis. Methods: Between 2012 and 2019, a voluntary survey was administered to participants and their caregivers to reflect on their perceptions of social/emotional well-being and protective factors related to chronic disease. T-tests compared change in participants' and caregivers' perceptions before and after camp; path analyses examined the key predictors of social-emotional well-being. Results: A total of 6011 online surveys were analyzed. Participants and caregivers reported consistently positive perceptions of participants' experiences during and after camp. Significant improvements in confidence, independence, activity, comfort around others, being more open about disease, and taking medication as expected were observed. Being new to Camp Oasis was one of the strongest predictors of both disease-related self-efficacy and social connections after camp. Conclusions: The uniformly high rates of participants' perceptions during camp suggest camp is a life-changing experience for youth with IBD, reduces disease-related stigma, and enhances confidence and social skills. Participants' positive experiences appear to foster notable benefits after camp in terms of openness, their sense of belonging, connections, and confidence.
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    Inhibition of APE1/Ref-1 Redox Signaling Alleviates Intestinal Dysfunction and Damage to Myenteric Neurons in a Mouse Model of Spontaneous Chronic Colitis
    (Oxford University Press, 2021-02-16) Sahakian, Lauren; Filippone, Rhiannon T.; Stavely, Rhian; Robinson, Ainsley M.; Yan, Xu Sean; Abalo, Raquel; Eri, Rajaraman; Bornstein, Joel C.; Kelley, Mark R.; Nurgali, Kulmira; Pediatrics, School of Medicine
    Background: Inflammatory bowel disease (IBD) associates with damage to the enteric nervous system (ENS), leading to gastrointestinal (GI) dysfunction. Oxidative stress is important for the pathophysiology of inflammation-induced enteric neuropathy and GI dysfunction. Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a dual functioning protein that is an essential regulator of the cellular response to oxidative stress. In this study, we aimed to determine whether an APE1/Ref-1 redox domain inhibitor, APX3330, alleviates inflammation-induced oxidative stress that leads to enteric neuropathy in the Winnie murine model of spontaneous chronic colitis. Methods: Winnie mice received APX3330 or vehicle via intraperitoneal injections over 2 weeks and were compared with C57BL/6 controls. In vivo disease activity and GI transit were evaluated. Ex vivo experiments were performed to assess functional parameters of colonic motility, immune cell infiltration, and changes to the ENS. Results: Targeting APE1/Ref-1 redox activity with APX3330 improved disease severity, reduced immune cell infiltration, restored GI function ,and provided neuroprotective effects to the enteric nervous system. Inhibition of APE1/Ref-1 redox signaling leading to reduced mitochondrial superoxide production, oxidative DNA damage, and translocation of high mobility group box 1 protein (HMGB1) was involved in neuroprotective effects of APX3330 in enteric neurons. Conclusions: This study is the first to investigate inhibition of APE1/Ref-1's redox activity via APX3330 in an animal model of chronic intestinal inflammation. Inhibition of the redox function of APE1/Ref-1 is a novel strategy that might lead to a possible application of APX3330 for the treatment of IBD.