title: IL-17 sequestration via salivary gland gene therapy in a mouse model of Sjogren's syndrome suppresses disease-associated expression of the putative autoantigen Klk1b22.
abstract: BACKGROUND
  IL-17 has a putative role in the pathophysiology of Sjogren's syndrome (SS) and has been shown to be upregulated in the salivary glands of affected individuals. Sequestration of IL-17 with Adenoviral-mediated gene therapy has previously shown a benefit upon the SS-like phenotype in the Aec1/Aec2 mouse model. We sought to understand the proteomic consequences of IL-17 sequestration in the salivary gland of this mouse model as a means of illuminating the role of IL-17 in SS-like disease.
  
  
  METHODS
  Ultrasound-assisted gene transfer (UAGT) was utilized to express a fusion protein composed of the extracellular portion of the IL-17 receptor fused to fragment of crystallization (Fc) in the submandibular glands of Aec1/Aec2 mice at 8 weeks of age. After confirming expression of the fusion protein and local and systemic sequestration of IL-17, proteomic profiling was performed on submandibular glands of a treated cohort of Aec1/Aec2 animals relative to the background strain and sham-treated animals.
  
  
  RESULTS
  The most notable proteomic signatures of IL-17 sequestration on SS-like disease-related proteins were Kallikrein-related peptidases, including the putative autoantigen Klk1b22. IL-17 sequestration also notably led to an isoelectric shift, but not a molecular weight shift, of Kallikrein-1, attributed to phosphorylation.
  
  
  CONCLUSIONS
  Non-viral IL-17 sequestration gene therapy in the salivary gland is feasible and downregulates expression of a putative SS autoantigen in the Aec1/Aec2 mouse.
authors.affiliation: Gene Therapy Program, Department of Medicine, Division of Cardiovascular Medicine, Allegheny Health Network, Room 841, South Tower, 320 East North Avenue, Pittsburgh, PA, 15212-4772, USA. cw1@wpahs.org.
authors.forename: Changgong
authors.initials: C
authors.lastname: Wu
authors.affiliation: Gene Therapy Program, Department of Medicine, Division of Cardiovascular Medicine, Allegheny Health Network, Room 841, South Tower, 320 East North Avenue, Pittsburgh, PA, 15212-4772, USA. zwang1@wpahs.org.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Gene Therapy Program, Department of Medicine, Division of Cardiovascular Medicine, Allegheny Health Network, Room 841, South Tower, 320 East North Avenue, Pittsburgh, PA, 15212-4772, USA. lzoureli@wpahs.org.
authors.forename: Lee
authors.initials: L
authors.lastname: Zourelias
authors.affiliation: Gene Therapy Program, Department of Medicine, Division of Cardiovascular Medicine, Allegheny Health Network, Room 841, South Tower, 320 East North Avenue, Pittsburgh, PA, 15212-4772, USA. hiteshi.s.thakker@gmail.com.
authors.forename: Hiteshi
authors.initials: H
authors.lastname: Thakker
authors.affiliation: Gene Therapy Program, Department of Medicine, Division of Cardiovascular Medicine, Allegheny Health Network, Room 841, South Tower, 320 East North Avenue, Pittsburgh, PA, 15212-4772, USA. mpassine@wpahs.org.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Passineau
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000096:biosynthesis; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods*; D020381:Interleukin-17 / Q000008:administration & dosage / Q000235:genetics; D007610:Kallikreins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D012469:Salivary Glands / Q000187:drug effects / Q000378:metabolism*; D012859:Sjogren's Syndrome / Q000235:genetics / Q000378:metabolism* / Q000628:therapy
chemical_list: D001324:Autoantigens; D020381:Interleukin-17; D007610:Kallikreins; C489121:Klk1b22 protein, mouse