title: AAV-IL-22 modifies liver chemokine activity and ameliorates portal inflammation in murine autoimmune cholangitis.
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.
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: fragrance0511@livemail.tw.
authors.forename: Yu-Hsin
authors.initials: YH
authors.lastname: Hsueh
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: brenda791010@gmail.com.
authors.forename: Yun-Ning
authors.initials: YN
authors.lastname: Chang
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: b97404049@ntu.edu.tw.
authors.forename: Chia-En
authors.initials: CE
authors.lastname: Loh
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA 95616, USA. Electronic address: megershwin@ucdavis.edu.
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: yahuichuang@ntu.edu.tw.
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Chuang
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000628:therapy*; D001691:Biological Therapy / Q000379:methods*; D054415:Chemokine CCL19 / Q000276:immunology / Q000378:metabolism; D018946:Chemokine CCL5 / Q000276:immunology / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000276:immunology / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000276:immunology / Q000378:metabolism; D002761:Cholangitis / Q000628:therapy*; D000229:Dependovirus; D004195:Disease Models, Animal; D005260:Female; D005699:Galactosylceramides / Q000276:immunology / Q000494:pharmacology; D005822:Genetic Vectors; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D008099:Liver / Q000098:blood supply / Q000276:immunology*; D008105:Liver Cirrhosis, Biliary / Q000276:immunology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D011168:Portal System / Q000276:immunology* / Q000473:pathology; D000097043:Interleukin-22
chemical_list: D054415:Chemokine CCL19; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D005699:Galactosylceramides; D007378:Interleukins; D000097043:Interleukin-22; C515461:Ccl19 protein, mouse; C503460:Ccl5 protein, mouse; C485433:Cxcl10 protein, mouse; C485969:Cxcl9 protein, mouse; C493154:alpha-galactosylceramide
keywords: Adeno-associated virus; Chemokine; IL-22; Liver autoimmune disease; Therapy