27 research outputs found
Osteopontin deletion drives hematopoietic stem cell mobilization to the liver and increases hepatic iron contributing to alcoholic liver disease.
The copy of record is available from the publisher at https://doi.org/10.1002/hep4.1116. Copyright © 2017 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Abstract: The aim of this study was to investigate the role of osteopontin (OPN) in hematopoietic stem cell (HPSC) mobilization to the liver and its contribution to alcoholic liver disease (ALD). We analyzed young (14â16 weeks) and old (\u3e1.5 years) wildâtype (WT) littermates and global Opn knockout (Opnâ/â) mice for HPSC mobilization to the liver. In addition, WT and Opnâ/â mice were chronically fed the LieberâDeCarli diet for 7 weeks. Bone marrow (BM), blood, spleen, and liver were analyzed by flow cytometry for HPSC progenitors and polymorphonuclear neutrophils (PMNs). Chemokines, growth factors, and cytokines were measured in serum and liver. Prussian blue staining for iron deposits and naphthol ASâD chloroacetate esterase staining for PMNs were performed on liver sections. Hematopoietic progenitors were lower in liver and BM of young compared to old Opnâ/â mice. Granulocyte colonyâstimulating factor and macrophage colonyâstimulating factor were increased in Opnâ/â mice, suggesting potential migration of HPSCs from the BM to the liver. Furthermore, ethanolâfed Opnâ/â mice showed significant hepatic PMN infiltration and hemosiderin compared to WT mice. As a result, ethanol feeding caused greater liver injury in Opnâ/â compared to WT mice. Conclusion: Opn deletion promotes HPSC mobilization, PMN infiltration, and iron deposits in the liver and thereby enhances the severity of ALD. The ageâassociated contribution of OPN to HPSC mobilization to the liver, the prevalence of PMNs, and accumulation of hepatic iron, which potentiates oxidant stress, reveal novel signaling mechanisms that could be targeted for therapeutic benefit in patients with ALD
Outcome of COVID-19 in Patients With Autoimmune Hepatitis: An International Multicenter Study
Background and Aims: Data regarding outcome of COVID-19 in patients with autoimmune hepatitis (AIH) are lacking. Approach and Results: We performed a retrospective study on patients with AIH and COVID-19 from 34 centers in Europe and the Americas. We analyzed factors associated with severe COVID-19 outcomes, defined as the need for mechanical ventilation, intensive care admission, and/or death. The outcomes of patients with AIH were compared to a propensity score?matched cohort of patients without AIH but with chronic liver diseases (CLD) and COVID-19. The frequency and clinical significance of new-onset liver injury (alanine aminotransferase > 2 Ă the upper limit of normal) during COVID-19 was also evaluated. We included 110 patients with AIH (80% female) with a median age of 49 (range, 18-85) years at COVID-19 diagnosis. New-onset liver injury was observed in 37.1% (33/89) of the patients. Use of antivirals was associated with liver injury (P = 0.041; OR, 3.36; 95% CI, 1.05-10.78), while continued immunosuppression during COVID-19 was associated with a lower rate of liver injury (P = 0.009; OR, 0.26; 95% CI, 0.09-0.71). The rates of severe COVID-19 (15.5% versus 20.2%, P = 0.231) and all-cause mortality (10% versus 11.5%, P = 0.852) were not different between AIH and non-AIH CLD. Cirrhosis was an independent predictor of severe COVID-19 in patients with AIH (P < 0.001; OR, 17.46; 95% CI, 4.22-72.13). Continuation of immunosuppression or presence of liver injury during COVID-19 was not associated with severe COVID-19. Conclusions: This international, multicenter study reveals that patients with AIH were not at risk for worse outcomes with COVID-19 than other causes of CLD. Cirrhosis was the strongest predictor for severe COVID-19 in patients with AIH. Maintenance of immunosuppression during COVID-19 was not associated with increased risk for severe COVID-19 but did lower the risk for new-onset liver injury during COVID-19.Fil: Efe, Cumali. Harran University Hospital; TurquĂaFil: Dhanasekaran, Renumathy. University of Stanford; Estados UnidosFil: Lammert, Craig. University School of Medicine; Estados UnidosFil: Ebik, Berat. Gazi YaĆargil Education and Research Hospital; TurquĂaFil: Higuera de la Tijera, Fatima. Hospital General de MĂ©xico; MĂ©xicoFil: Aloman, Costica. Rush University Medical Center; Estados UnidosFil: Rıza CalıĆkan, Ali. Adıyaman University; TurquĂaFil: Peralta, Mirta. Latin American Liver Research Educational And Awareness Network; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Gerussi, Alessio. University of Milano Bicocca; Italia. San Gerardo Hospital; ItaliaFil: Massoumi, Hatef. Montefiore Medical Center; Estados UnidosFil: Catana, Andreea M.. Harvard Medical School; Estados UnidosFil: Torgutalp, Murat. UniversitĂ€tsmedizin Berlin; AlemaniaFil: Purnak, Tugrul. McGovern Medical School; Estados UnidosFil: Rigamonti, Cristina. Azienda Ospedaliera Maggiore Della Carita Di Novara; Italia. UniversitĂ del Piemonte Orientale; ItaliaFil: Gomez Aldana, Andres Jose. Universidad de los Andes; ColombiaFil: Khakoo, Nidah. University of Miami; Estados UnidosFil: Kacmaz, HĂŒseyin. Adıyaman University; TurquĂaFil: Nazal, Leyla. ClĂnica Las Condes; ChileFil: Frager, Shalom. Montefiore Medical Center; Estados UnidosFil: Demir, Nurhan. Haseki Training and Research Hospita; TurquĂaFil: Irak, Kader. SBU Kanuni Sultan SĂŒleyman Training and Research Hospital; TurquĂaFil: Ellik, Zeynep MelekoÄlu. Ankara University Medical Faculty; TurquĂaFil: Balaban, Yasemin. Hacettepe University; TurquĂaFil: Atay, Kadri. Mardin State Hospital; TurquĂaFil: Eren, Fatih. Ordu State Hospital; TurquĂaFil: Cristoferi, Laura. University of Milano Bicocca; Italia. San Gerardo Hospital; ItaliaFil: Batibay, Ersin. Harran University Hospital; TurquĂaFil: Urzua, Ălvaro. Universidad de Chile. Facultad de Medicina.; ChileFil: Snijders, Romee. Radboud University Medical Center; PaĂses BajosFil: Ridruejo, Ezequiel. Latin American Liver Research Educational and Awareness Network; Argentina. CerrahpaĆa School of Medicine; TurquĂa. Centro de EducaciĂłn MĂ©dica e Investigaciones ClĂnicas "Norberto Quirno"; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; Argentin
Effects of immunosuppressive drugs on COVID-19 severity in patients with autoimmune hepatitis
Background: We investigated associations between baseline use of immunosuppressive drugs and severity of Coronavirus Disease 2019 (COVID-19) in autoimmune hepatitis (AIH). Patients and methods: Data of AIH patients with laboratory confirmed COVID-19 were retrospectively collected from 15 countries. The outcomes of AIH patients who were on immunosuppression at the time of COVID-19 were compared to patients who were not on AIH medication. The clinical courses of COVID-19 were classified as (i)-no hospitalization, (ii)-hospitalization without oxygen supplementation, (iii)-hospitalization with oxygen supplementation by nasal cannula or mask, (iv)-intensive care unit (ICU) admission with non-invasive mechanical ventilation, (v)-ICU admission with invasive mechanical ventilation or (vi)-death and analysed using ordinal logistic regression. Results: We included 254 AIH patients (79.5%, female) with a median age of 50 (range, 17-85) years. At the onset of COVID-19, 234 patients (92.1%) were on treatment with glucocorticoids (n = 156), thiopurines (n = 151), mycophenolate mofetil (n = 22) or tacrolimus (n = 16), alone or in combinations. Overall, 94 (37%) patients were hospitalized and 18 (7.1%) patients died. Use of systemic glucocorticoids (adjusted odds ratio [aOR] 4.73, 95% CI 1.12-25.89) and thiopurines (aOR 4.78, 95% CI 1.33-23.50) for AIH was associated with worse COVID-19 severity, after adjusting for age-sex, comorbidities and presence of cirrhosis. Baseline treatment with mycophenolate mofetil (aOR 3.56, 95% CI 0.76-20.56) and tacrolimus (aOR 4.09, 95% CI 0.69-27.00) were also associated with more severe COVID-19 courses in a smaller subset of treated patients. Conclusion: Baseline treatment with systemic glucocorticoids or thiopurines prior to the onset of COVID-19 was significantly associated with COVID-19 severity in patients with AIH.Fil: Efe, Cumali. Harran University Hospita; TurquĂaFil: Lammert, Craig. University School of Medicine Indianapolis; Estados UnidosFil: TaĆçılar, Koray. Universitat Erlangen-Nuremberg; AlemaniaFil: Dhanasekaran, Renumathy. University of Stanford; Estados UnidosFil: Ebik, Berat. Gazi Yasargil Education And Research Hospital; TurquĂaFil: Higuera de la Tijera, Fatima. Hospital General de MĂ©xico; MĂ©xicoFil: CalıĆkan, Ali R.. No especifĂca;Fil: Peralta, Mirta. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Gerussi, Alessio. UniversitĂ degli Studi di Milano; ItaliaFil: Massoumi, Hatef. No especifĂca;Fil: Catana, Andreea M.. Harvard Medical School; Estados UnidosFil: Purnak, Tugrul. University of Texas; Estados UnidosFil: Rigamonti, Cristina. UniversitĂ del Piemonte Orientale ; ItaliaFil: Aldana, Andres J. G.. Fundacion Santa Fe de Bogota; ColombiaFil: Khakoo, Nidah. Miami University; Estados UnidosFil: Nazal, Leyla. Clinica Las Condes; ChileFil: Frager, Shalom. Montefiore Medical Center; Estados UnidosFil: Demir, Nurhan. Haseki Training And Research Hospital; TurquĂaFil: Irak, Kader. Kanuni Sultan Suleyman Training And Research Hospital; TurquĂaFil: MelekoÄlu Ellik, Zeynep. Ankara University Medical Faculty; TurquĂaFil: Kacmaz, HĂŒseyin. Adıyaman University; TurquĂaFil: Balaban, Yasemin. Hacettepe University; TurquĂaFil: Atay, Kadri. No especifĂca;Fil: Eren, Fatih. No especifĂca;Fil: Alvares da-Silva, Mario R.. Universidade Federal do Rio Grande do Sul; BrasilFil: Cristoferi, Laura. UniversitĂ degli Studi di Milano; ItaliaFil: Urzua, Ălvaro. Universidad de Chile; ChileFil: EĆkazan, TuÄçe. CerrahpaĆa School of Medicine; TurquĂaFil: Magro, Bianca. No especifĂca;Fil: Snijders, Romee. No especifĂca;Fil: Barutçu, Sezgin. No especifĂca;Fil: Lytvyak, Ellina. University of Alberta; CanadĂĄFil: Zazueta, Godolfino M.. Instituto Nacional de la NutriciĂłn Salvador Zubiran; MĂ©xicoFil: Demirezer Bolat, Aylin. Ankara City Hospital; TurquĂaFil: Aydın, Mesut. Van Yuzuncu Yil University; TurquĂaFil: AmorĂłs MartĂn, Alexandra NoemĂ. No especifĂca;Fil: De Martin, Eleonora. No especifĂca;Fil: Ekin, Nazım. No especifĂca;Fil: Yıldırım, SĂŒmeyra. No especifĂca;Fil: Yavuz, Ahmet. No especifĂca;Fil: Bıyık, Murat. Necmettin Erbakan University; TurquĂaFil: Narro, Graciela C.. Instituto Nacional de la NutriciĂłn Salvador Zubiran; MĂ©xicoFil: Bıyık, Murat. Uludag University; TurquĂaFil: Kıyıcı, Murat. No especifĂca;Fil: KahramanoÄlu Aksoy, Evrim. No especifĂca;Fil: Vincent, Maria. No especifĂca;Fil: Carr, Rotonya M.. University of Pennsylvania; Estados UnidosFil: GĂŒnĆar, Fulya. No especifĂca;Fil: Reyes, Eira C.. Hepatology Unit. Hospital Militar Central de MĂ©xico; MĂ©xicoFil: HarputluoÄlu, Murat. InönĂŒ University School of Medicine; TurquĂaFil: Aloman, Costica. Rush University Medical Center; Estados UnidosFil: Gatselis, Nikolaos K.. University Hospital Of Larissa; GreciaFil: ĂstĂŒndaÄ, YĂŒcel. No especifĂca;Fil: Brahm, Javier. Clinica Las Condes; ChileFil: Vargas, Nataly C. E.. Hospital Nacional Almanzor Aguinaga Asenjo; PerĂșFil: GĂŒzelbulut, Fatih. No especifĂca;Fil: Garcia, Sandro R.. Hospital Iv VĂctor Lazarte Echegaray; PerĂșFil: Aguirre, Jonathan. Hospital Angeles del Pedregal; MĂ©xicoFil: Anders, Margarita. Hospital AlemĂĄn; ArgentinaFil: Ratusnu, Natalia. Hospital Regional de Ushuaia; ArgentinaFil: Hatemi, Ibrahim. No especifĂca;Fil: Mendizabal, Manuel. Universidad Austral; ArgentinaFil: Floreani, Annarosa. UniversitĂ di Padova; ItaliaFil: Fagiuoli, Stefano. No especifĂca;Fil: Silva, Marcelo. Universidad Austral; ArgentinaFil: Idilman, Ramazan. No especifĂca;Fil: Satapathy, Sanjaya K.. No especifĂca;Fil: Silveira, Marina. University of Yale. School of Medicine; Estados UnidosFil: Drenth, Joost P. H.. No especifĂca;Fil: Dalekos, George N.. No especifĂca;Fil: N.Assis, David. University of Yale. School of Medicine; Estados UnidosFil: Björnsson, Einar. No especifĂca;Fil: Boyer, James L.. University of Yale. School of Medicine; Estados UnidosFil: Yoshida, Eric M.. University of British Columbia; CanadĂĄFil: Invernizzi, Pietro. UniversitĂ degli Studi di Milano; ItaliaFil: Levy, Cynthia. University of Miami; Estados UnidosFil: Montano Loza, Aldo J.. University of Alberta; CanadĂĄFil: Schiano, Thomas D.. No especifĂca;Fil: Ridruejo, Ezequiel. Universidad Austral; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones MĂ©dicas e Investigaciones ClĂnicas "Norberto Quirno". CEMIC-CONICET; ArgentinaFil: Wahlin, Staffan. No especifĂca
GM-CSF Controls Nonlymphoid Tissue Dendritic Cell Homeostasis but Is Dispensable for the Differentiation of Inflammatory Dendritic Cells
SummaryGM-CSF (Csf-2) is a critical cytokine for the in vitro generation of dendritic cells (DCs) and is thought to control the development of inflammatory DCs and resident CD103+ DCs in some tissues. Here we showed that in contrast to the current understanding, Csf-2 receptor acts in the steady state to promote the survival and homeostasis of nonlymphoid tissue-resident CD103+ and CD11b+ DCs. Absence of Csf-2 receptor on lung DCs abrogated the induction of CD8+ T cell immunity after immunization with particulate antigens. In contrast, Csf-2 receptor was dispensable for the differentiation and innate function of inflammatory DCs during acute injuries. Instead, inflammatory DCs required Csf-1 receptor for their development. Thus, Csf-2 is important in vaccine-induced CD8+ T cell immunity through the regulation of nonlymphoid tissue DC homeostasis rather than control of inflammatory DCs in vivo
Generation of Immune Responses against Hepatitis C Virus by Dendritic Cells Containing NS5 Protein-Coated Microparticles âż
Dendritic cells (DCs) internalize and process antigens as well as activate cellular immune responses. The aim of this study was to determine the capacity of DCs that contain antigen-coated magnetic beads to induce immunity against the nonstructural hepatitis C virus (HCV) antigen 5 (NS5). Splenocytes derived from Fms-like tyrosine kinase receptor 3 (Flt3) ligand-pretreated BALB/c mice were incubated with magnetic beads coated with HCV NS5, lipopolysaccharide (LPS), and/or anti-CD40; purified; and used for immunization. Cellular immunity was measured using cytotoxic T-lymphocyte (CTL) and T-cell proliferation assays, intracellular cytokine staining, and a syngeneic tumor challenge using NS5-expressing SP2/0 myeloma cells in vivo. Splenocytes isolated from animals vaccinated with DCs containing beads coated with NS5, LPS, and anti-CD40 secreted elevated levels of interleukin-2 (IL-2) and gamma interferon in the presence of NS5. The numbers of CD4+, IL-2-producing cells were increased >5-fold in the group immunized with DCs containing beads coated with NS5, LPS, and anti-CD40, paralleled by an enhanced splenocyte proliferative response. Immunization promoted antigen-specific CTL activity threefold compared to the level for control mice and significantly reduced the growth of NS5-expressing tumor cells in vivo. Thus, strategies that employ NS5-coated beads induce cellular immune responses in mice, which correlate well with the natural immune responses that occur in individuals who resolve HCV
Hepatitis C infection and alcohol use: A dangerous mix for the liver and antiviral immunity
This article presents the proceedings of a symposium presented at the meeting of the Research Society on Alcoholism, held in Santa Barbara, California, in June 2005. The organizers and chairs were Sam Zakhari and Gyongyi Szabo. The presentations included (1) Mitochondrial Abnormalities Induced by Hepatitis C -Alcohol Interaction by Steven Weinman; (2) Effects of Acute and Chronic Ethanol on Innate Antiviral Signaling Pathways, Hepatitis C Replication, and Human Liver Cell Transcription by Stephen Polyak; (3) Ethanol Alters Dendritic Cell Function In Vivo and Impairs the Subsequent Cellular Immune Responses to Hepatitis C Proteins by Costica Aloman; and (4) Pathogenic Interactions Between Hepatitis C Virus and Alcohol Use in Humans: Dendritic Cells as Common Targets by Gyongyi Szabo. This symposium summarizes the state of knowledge of cellular and molecular pathways by which alcohol and HCV have pathogenic interactions resulting in depression of the immune response and liver damage in chronic HCV infection
Osteopontin deletion drives hematopoietic stem cell mobilization to the liver and increases hepatic iron contributing to alcoholic liver disease
The copy of record is available from the publisher at https://doi.org/10.1002/hep4.1116. Copyright © 2017 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Abstract: The aim of this study was to investigate the role of osteopontin (OPN) in hematopoietic stem cell (HPSC) mobilization to the liver and its contribution to alcoholic liver disease (ALD). We analyzed young (14â16 weeks) and old (\u3e1.5 years) wildâtype (WT) littermates and global Opn knockout (Opnâ/â) mice for HPSC mobilization to the liver. In addition, WT and Opnâ/â mice were chronically fed the LieberâDeCarli diet for 7 weeks. Bone marrow (BM), blood, spleen, and liver were analyzed by flow cytometry for HPSC progenitors and polymorphonuclear neutrophils (PMNs). Chemokines, growth factors, and cytokines were measured in serum and liver. Prussian blue staining for iron deposits and naphthol ASâD chloroacetate esterase staining for PMNs were performed on liver sections. Hematopoietic progenitors were lower in liver and BM of young compared to old Opnâ/â mice. Granulocyte colonyâstimulating factor and macrophage colonyâstimulating factor were increased in Opnâ/â mice, suggesting potential migration of HPSCs from the BM to the liver. Furthermore, ethanolâfed Opnâ/â mice showed significant hepatic PMN infiltration and hemosiderin compared to WT mice. As a result, ethanol feeding caused greater liver injury in Opnâ/â compared to WT mice. Conclusion: Opn deletion promotes HPSC mobilization, PMN infiltration, and iron deposits in the liver and thereby enhances the severity of ALD. The ageâassociated contribution of OPN to HPSC mobilization to the liver, the prevalence of PMNs, and accumulation of hepatic iron, which potentiates oxidant stress, reveal novel signaling mechanisms that could be targeted for therapeutic benefit in patients with ALD
A novel murine model to deplete hepatic stellate cells uncovers their role in amplifying liver damage in mice
UnlabelledWe have developed a novel model for depleting mouse hepatic stellate cells (HSCs) that has allowed us to clarify their contributions to hepatic injury and fibrosis. Transgenic (Tg) mice expressing the herpes simplex virus thymidine kinase gene (HSV-Tk) driven by the mouse GFAP promoter were used to render proliferating HSCs susceptible to killing in response to ganciclovir (GCV). Effects of GCV were explored in primary HSCs and in vivo. Panlobular damage was provoked to maximize HSC depletion by combining CCl(4) (centrilobular injury) with allyl alcohol (AA) (periportal injury), as well as in a bile duct ligation (BDL) model. Cell depletion in situ was quantified using dual immunofluorescence (IF) for desmin and GFAP. In primary HSCs isolated from both untreated wild-type (WT) and Tg mice, GCV induced cell death in â 50% of HSCs from Tg, but not WT, mice. In TG mice treated with CCl(4) +AA+GCV, there was a significant decrease in GFAP and desmin-positive cells, compared to WT mice (â 65% reduction; P < 0.01), which was accompanied by a decrease in the expression of HSC-activation markers (alpha smooth muscle actin, beta platelet-derived growth factor receptor, and collagen I). Similar results were observed after BDL. Associated with HSC depletion in both fibrosis models, there was marked attenuation of fibrosis and liver injury, as indicated by Sirius Red/Fast Green, hematoxylin and eosin quantification, and serum alanine/aspartate aminotransferase. Hepatic expression of interleukin-10 and interferon-gamma was increased after HSC depletion. No toxicity of GCV in either WT or Tg mice accounted for the differences in injury.ConclusionActivated HSCs significantly amplify the response to liver injury, further expanding this cell type's repertoire in orchestrating hepatic injury and repair