AAV-IL-22 modifies liver chemokine activity and ameliorates portal inflammation in murine autoimmune cholangitis |
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| Affiliation: | 1. Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan;2. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA 95616, USA;1. Dept. of Medical, Surgical and Health Sciences, University of Trieste, Italy;2. Dept of Nuclear Medicine, Azienda Ospedaliero-Universitaria Ospedali Riuniti, Trieste, Italy;3. Molecular Medicine Laboratory, International Centre for Genetics, Engineering and Biotechnology, Trieste, Italy;1. Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain;2. Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, USA;3. Department of Pathology, Georgetown University Medical Center, Washington, DC, USA;4. Division of Comparative Medicine, Georgetown University Medical Center, Washington, DC, USA;1. Department of Clinical Physiology and Nuclear Medicine, Center of Functional and Diagnostic Imaging and Research, Copenhagen University, Hvidovre, Denmark;2. Gastro Unit, Medical Division, Hvidovre University Hospital, Faculty of Health Sciences, Copenhagen University, Hvidovre, Denmark;1. Dept. of Pathology (Division of Experimental Pathology), University of Pittsburgh, Pittsburgh, PA, United States;2. McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States |
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| Abstract: | ![]()
There remain significant obstacles in developing biologics to treat primary biliary cholangitis (PBC). Although a number of agents have been studied both in murine models and human patients, the results have been relatively disappointing. IL-22 is a member of the IL-10 family and has multiple theoretical reasons for predicting successful usage in PBC. We have taken advantage of an IL-22 expressing adeno-associated virus (AAV-IL-22) to address the potential role of IL-22 in not only protecting mice from autoimmune cholangitis, but also in treating animals with established portal inflammation. Using our established mouse model of 2-OA-OVA immunization, including α-galactosylceramide (α-GalCer) stimulation, we treated mice both before and after the onset of clinical disease with AAV-IL-22. Firstly, AAV-IL-22 treatment given prior to 2-OA-OVA and α-GalCer exposure, i.e. before the onset of disease, significantly reduces the portal inflammatory response, production of Th1 cytokines and appearance of liver fibrosis. It also reduced the liver lymphotropic chemokines CCL5, CCL19, CXCL9, and CXCL10. Secondly, and more importantly, therapeutic use of AAV-IL-22, administered after the onset of disease, achieved a greater hurdle and significantly improved portal pathology. Further the improvements in inflammation were negatively correlated with levels of CCL5 and CXCL10 and positively correlated with levels of IL-22. In conclusion, we submit that the clinical use of IL-22 has a potential role in modulating the inflammatory portal process in patients with PBC. |
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| Keywords: | IL-22 Liver autoimmune disease Adeno-associated virus Chemokine Therapy 2-OA-OVA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0040" }," $$" :[{" #name" :" text" ," _" :" 2-octynoic acid conjugated ovalbumin AAV" },{" #name" :" keyword" ," $" :{" id" :" kwrd0050" }," $$" :[{" #name" :" text" ," _" :" adeno-associated virus AMAs" },{" #name" :" keyword" ," $" :{" id" :" kwrd0060" }," $$" :[{" #name" :" text" ," _" :" anti-mitochondrial antibodies MNCs" },{" #name" :" keyword" ," $" :{" id" :" kwrd0070" }," $$" :[{" #name" :" text" ," _" :" mononuclear cells PBC" },{" #name" :" keyword" ," $" :{" id" :" kwrd0080" }," $$" :[{" #name" :" text" ," _" :" primary biliary cholangitis TU" },{" #name" :" keyword" ," $" :{" id" :" kwrd0090" }," $$" :[{" #name" :" text" ," _" :" transduction unit |
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