title: Comparison of IL-10 and MCP-1-7ND gene transfer with AAV9 vectors for protection from murine autoimmune myocarditis.
abstract: OBJECTIVE
  Overexpression of therapeutic genes with potential disease-limiting effects, specifically at the site of inflammation, remains a major clinical challenge. In this study, we investigate the potential of adeno-associated virus (AAV)-9-mediated cardiac expression of the anti-inflammatory mediators interleukin (IL)-10 and a dominant-negative inhibitor of monocyte chemoattractant protein-1 (MCP1-7ND) on prevention of autoimmune myocarditis.
  
  
  RESULTS
  Autoimmune myocarditis was induced by immunizing A/J mice with subcutaneous injection of 120 µg cardiac troponin I (cTnI) on Days 0, 7, and 14. Two weeks prior to initial immunization, each mouse received a single systemic dose of 10(12) AAV9 vectors carrying the coding sequence of IL-10 or MCP1-7ND transcriptionally targeted to the heart. Mice were sacrificed 28 days after initial immunization for further analysis. Only expression of IL-10 resulted in a highly significant decrease in myocardial inflammation and fibrosis, as well as an increased ejection fraction compared with controls. Further analyses of cytokine profiles of cTnI-stimulated splenocytes from IL-10 and MCP1-7ND-treated mice revealed significant alterations compared with controls. In addition, transcript levels of chemokine receptor CCR4 and T-cell activation gene were significantly reduced in hearts of IL-10-treated mice as determined by quantitative real-time PCR.
  
  
  CONCLUSIONS
  Our study suggests that cardiac expression of IL-10 with AAV9 vectors is a promising therapeutic approach for autoimmune myocarditis.
authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. ziya.kaya@med.uni-heidelberg.de
authors.forename: Ziya
authors.initials: Z
authors.lastname: Kaya
authors.forename: Christoph
authors.initials: C
authors.lastname: Leib
authors.forename: Stanislas
authors.initials: S
authors.lastname: Werfel
authors.forename: Stefan
authors.initials: S
authors.lastname: Göser
authors.forename: Renate
authors.initials: R
authors.lastname: Öttl
authors.forename: Barbara
authors.initials: B
authors.lastname: Leuchs
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pfitzer
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Müller
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D056724:Immunity, Humoral / Q000235:genetics; D007275:Injections, Intravenous; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D051379:Mice; D009205:Myocarditis / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000276:immunology* / Q000473:pathology; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D019210:Troponin I; D016277:Ventricular Function, Left
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; C556062:IL10 protein, mouse; D019707:Receptors, Chemokine; D019210:Troponin I; D016753:Interleukin-10