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      Pilot study of lithium to restore intestinal barrier function in severe graft-versus-host disease

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          Abstract

          Severe intestinal graft-vs-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) causes mucosal ulceration and induces innate and adaptive immune responses that amplify and perpetuate GVHD and the associated barrier dysfunction. Pharmacological agents to target mucosal barrier dysfunction in GVHD are needed. We hypothesized that induction of Wnt signaling by lithium, an inhibitor of glycogen synthase kinase (GSK3), would potentiate intestinal crypt proliferation and mucosal repair and that inhibition of GSK3 in inflammatory cells would attenuate the deregulated inflammatory response to mucosal injury. We conducted an observational pilot study to provide data for the potential design of a randomized study of lithium. Twenty patients with steroid refractory intestinal GVHD meeting enrollment criteria were given oral lithium carbonate. GVHD was otherwise treated per current practice, including 2 mg/kg per day of prednisone equivalent. Seventeen patients had extensive mucosal denudation (extreme endoscopic grade 3) in the duodenum or colon. We observed that 8 of 12 patients (67%) had a complete remission (CR) of GVHD and survived more than 1 year (median 5 years) when lithium administration was started promptly within 3 days of endoscopic diagnosis of denuded mucosa. When lithium was started promptly and less than 7 days from salvage therapy for refractory GVHD, 8 of 10 patients (80%) had a CR and survived more than 1 year. In perspective, a review of 1447 consecutive adult HCT patients in the preceding 6 years at our cancer center showed 0% one-year survival in 27 patients with stage 3–4 intestinal GVHD and grade 3 endoscopic appearance in the duodenum or colon. Toxicities included fatigue, somnolence, confusion or blunted affect in 50% of the patients. The favorable outcomes in patients who received prompt lithium therapy appear to support the future conduct of a randomized study of lithium for management of severe GVHD with extensive mucosal injury.

          Trial Registration: ClinicalTrials.gov NCT00408681

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          Most cited references 48

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          Reduced mortality after allogeneic hematopoietic-cell transplantation.

          Over the past decade, advances have been made in the care of patients undergoing transplantation. We conducted a study to determine whether these advances have improved the outcomes of transplantation. We analyzed overall mortality, mortality not preceded by relapse, recurrent malignant conditions, and the frequency and severity of major complications of transplantation, including graft-versus-host disease (GVHD) and hepatic, renal, pulmonary, and infectious complications, among 1418 patients who received their first allogeneic transplants at our center in Seattle in the period from 1993 through 1997 and among 1148 patients who received their first allogeneic transplants in the period from 2003 through 2007. Components of the Pretransplant Assessment of Mortality (PAM) score were used in regression models to adjust for the severity of illness at the time of transplantation. In the 2003-2007 period, as compared with the 1993-1997 period, we observed significant decreases in mortality not preceded by relapse, both at day 200 (by 60%) and overall (by 52%), the rate of relapse or progression of a malignant condition (by 21%), and overall mortality (by 41%), after adjustment for components of the PAM score. The results were similar when the analyses were limited to patients who received myeloablative conditioning therapy. We also found significant decreases in the risk of severe GVHD; disease caused by viral, bacterial, and fungal infections; and damage to the liver, kidneys, and lungs. We found a substantial reduction in the hazard of death related to allogeneic hematopoietic-cell transplantation, as well as increased long-term survival, over the past decade. Improved outcomes appear to be related to reductions in organ damage, infection, and severe acute GVHD. (Funded by the National Institutes of Health.).
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            Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3.

            The cellular mechanisms that directly regulate the inflammatory response after Toll-like receptor (TLR) stimulation are unresolved at present. Here we report that glycogen synthase kinase 3 (GSK3) differentially regulates TLR-mediated production of pro- and anti-inflammatory cytokines. Stimulation of monocytes or peripheral blood mononuclear cells with TLR2, TLR4, TLR5 or TLR9 agonists induced substantial increases in interleukin 10 production while suppressing the release of proinflammatory cytokines after GSK3 inhibition. GSK3 regulated the inflammatory response by differentially affecting the nuclear amounts of transcription factors NF-kappaB subunit p65 and CREB interacting with the coactivator CBP. Administration of a GSK3 inhibitor potently suppressed the proinflammatory response in mice receiving lipopolysaccharide and mediated protection from endotoxin shock. These findings demonstrate a regulatory function for GSK3 in modulating the inflammatory response.
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              A molecular mechanism for the effect of lithium on development.

              Lithium, one of the most effective drugs for the treatment of bipolar (manic-depressive) disorder, also has dramatic effects on morphogenesis in the early development of numerous organisms. How lithium exerts these diverse effects is unclear, but the favored hypothesis is that lithium acts through inhibition of inositol monophosphatase (IMPase). We show here that complete inhibition of IMPase has no effect on the morphogenesis of Xenopus embryos and present a different hypothesis to explain the broad action of lithium. Our results suggest that lithium acts through inhibition of glycogen synthase kinase-3 beta (GSK-3 beta), which regulates cell fate determination in diverse organisms including Dictyostelium, Drosophila, and Xenopus. Lithium potently inhibits GSK-3 beta activity (Ki = 2 mM), but is not a general inhibitor of other protein kinases. In support of this hypothesis, lithium treatment phenocopies loss of GSK-3 beta function in Xenopus and Dictyostelium. These observations help explain the effect of lithium on cell-fate determination and could provide insights into the pathogenesis and treatment of bipolar disorder.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                17 August 2017
                2017
                : 12
                : 8
                Affiliations
                [1 ] Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
                [2 ] Department of Medicine, University of Washington, Seattle, Washington, United States of America
                [3 ] Department of Haematology, Radboud University Medical Center, Nijmegen, The Netherlands
                [4 ] Department of Pathology, University of Washington, Seattle, Washington, United States of America
                [5 ] Department of Psychiatry, University of Washington, Seattle, Washington, United States of America
                Jackson Laboratory, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: GS GH PJM.

                • Data curation: TF CC-L.

                • Funding acquisition: PJM GBM.

                • Investigation: GS DMH GH TF DM KRL JRF GBM PJM.

                • Methodology: GS DMH GH TF DM KRL JRF CC-L GBM PJM.

                • Resources: GS DMH TF DM KRL JRF CC-L GBM PJM.

                • Validation: GS TF DM KRL JRF CC-L PJM.

                • Writing – original draft: GS PJM.

                • Writing – review & editing: GS DMH GH TF DM KRL JRF CC-L GBM PJM.

                [¤]

                Current address: Service d´Hématologie, Institut Gustave Roussy, Villejuif, France

                Article
                PONE-D-15-26847
                10.1371/journal.pone.0183284
                5560707
                28817727
                © 2017 Steinbach et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 2, Tables: 6, Pages: 18
                Product
                Funding
                Funded by: National Institutes of Health (US) (partial funding)
                Award ID: CA18029
                This study was supported by grant CA18029 from the National Institutes of Health, Department of Health and Human Services (partial funding). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Physical Sciences
                Chemistry
                Chemical Elements
                Lithium
                Biology and Life Sciences
                Anatomy
                Digestive System
                Gastrointestinal Tract
                Medicine and Health Sciences
                Anatomy
                Digestive System
                Gastrointestinal Tract
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Endoscopy
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Hematologic Cancers and Related Disorders
                Myelomas and Lymphoproliferative Diseases
                Myelomas
                Multiple Myeloma
                Medicine and Health Sciences
                Hematology
                Hematologic Cancers and Related Disorders
                Myelomas and Lymphoproliferative Diseases
                Myelomas
                Multiple Myeloma
                Medicine and Health Sciences
                Hematology
                Plasma Cell Disorders
                Multiple Myeloma
                Biology and Life Sciences
                Cell Biology
                Signal Transduction
                Cell Signaling
                Signaling Cascades
                WNT Signaling Cascade
                Biology and Life Sciences
                Toxicology
                Toxicity
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Toxicology
                Toxicity
                Biology and Life Sciences
                Anatomy
                Digestive System
                Gastrointestinal Tract
                Duodenum
                Medicine and Health Sciences
                Anatomy
                Digestive System
                Gastrointestinal Tract
                Duodenum
                Biology and Life Sciences
                Anatomy
                Digestive System
                Gastrointestinal Tract
                Colon
                Medicine and Health Sciences
                Anatomy
                Digestive System
                Gastrointestinal Tract
                Colon
                Custom metadata
                The authors attempted to provide all relevant data within the manuscript, tables, figures and Supporting Information, and will provide available additional data for publication or online appendix at the request of the editors. All the necessary underlying data that are not ethically restricted have been provided. Confidential, patient related source data for IRB protocol 2080 would be available from the Fred Hutchinson Cancer Research Center IRB for researchers who meet the criteria for access to confidential data. Address requests for protocol 2080.00 confidential data to: Fred Hutchinson Cancer Research Center; Institutional Review Office; PO Box 19024, J2-100; Seattle, WA 98109-1024; https://extranet.fredhutch.org/en/u/iro/contact-information.html.

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