title: Pristane-Accelerated Autoimmune Disease in (SWR X NZB) F1 Mice Leads to Prominent Tubulointerstitial Inflammation and Human Lupus Nephritis-Like Fibrosis.
abstract: Mouse models lupus nephritis (LN) have provided important insights into disease pathogenesis, although none have been able to recapitulate all features of the human disease. Using comprehensive longitudinal analyses, we characterized a novel accelerated mouse model of lupus using pristane treatment in SNF1 (SWR X NZB F1) lupus prone mice (pristane-SNF1 mice). Pristane treatment in SNF1 mice accelerated the onset and progression of proteinuria, autoantibody production, immune complex deposition and development of renal lesions. At week 14, the pristane-SNF1 model recapitulated kidney disease parameters and molecular signatures seen in spontaneous disease in 36 week-old SNF1 mice and in a traditional IFNα-accelerated NZB X NZW F1 (BWF1) model. Blood transcriptome analysis revealed interferon, plasma cell, neutrophil, T-cell and protein synthesis signatures in the pristane-SNF1 model, all known to be present in the human disease. The pristane-SNF1 model appears to be particularly useful for preclinical research, robustly exhibiting many characteristics reminiscent of human disease. These include i) a stronger upregulation of the cytosolic nucleic acid sensing pathway, which is thought to be key component of the pathogenesis of the human disease, and ii) more prominent kidney interstitial inflammation and fibrosis, which have been both associated with poor prognosis in human LN. To our knowledge, this is the only accelerated model of LN that exhibits a robust tubulointerstitial inflammatory and fibrosis response. Taken together our data show that the pristane-SNF1 model is a novel accelerated model of LN with key features similar to human disease.
authors.affiliation: Biogen, Cambridge, Massachusetts, United States of America.
authors.forename: Agnes
authors.initials: A
authors.lastname: Gardet
authors.affiliation: Biogen, Cambridge, Massachusetts, United States of America.
authors.forename: Wei C
authors.initials: WC
authors.lastname: Chou
authors.affiliation: Biogen, Cambridge, Massachusetts, United States of America.
authors.forename: Taylor L
authors.initials: TL
authors.lastname: Reynolds
authors.affiliation: Biogen, Cambridge, Massachusetts, United States of America.
authors.forename: Diana B
authors.initials: DB
authors.lastname: Velez
authors.affiliation: Biogen, Cambridge, Massachusetts, United States of America.
authors.forename: Kai
authors.initials: K
authors.lastname: Fu
authors.affiliation: Biogen, Cambridge, Massachusetts, United States of America.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Czerkowicz
authors.affiliation: Biogen, Cambridge, Massachusetts, United States of America.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Bajko
authors.affiliation: Biogen, Cambridge, Massachusetts, United States of America.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Ranger
authors.affiliation: Biogen, Cambridge, Massachusetts, United States of America.
authors.forename: Normand
authors.initials: N
authors.lastname: Allaire
authors.affiliation: Biogen, Cambridge, Massachusetts, United States of America.
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Kerns
authors.affiliation: Biogen, Cambridge, Massachusetts, United States of America.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ryan
authors.affiliation: Biogen, Cambridge, Massachusetts, United States of America.
authors.forename: Holly M
authors.initials: HM
authors.lastname: Legault
authors.affiliation: Biogen, Cambridge, Massachusetts, United States of America.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Dunstan
authors.affiliation: Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Lafyatis
authors.affiliation: Biogen, Cambridge, Massachusetts, United States of America.
authors.forename: Matvey
authors.initials: M
authors.lastname: Lukashev
authors.affiliation: Biogen, Cambridge, Massachusetts, United States of America.
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Viney
authors.affiliation: Boston University School of Medicine, Department of Microbiology, Boston, United States of America.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Browning
authors.affiliation: Biogen, Cambridge, Massachusetts, United States of America.
authors.forename: Dania
authors.initials: D
authors.lastname: Rabah
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005355:Fibrosis; D005921:Glomerulonephritis / Q000139:chemically induced / Q000150:complications; D006801:Humans; D006942:Hypergammaglobulinemia / Q000139:chemically induced / Q000150:complications; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D007684:Kidney Tubules / Q000187:drug effects* / Q000473:pathology*; D008181:Lupus Nephritis / Q000150:complications / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D013729:Terpenes / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D000099197:STING Protein
chemical_list: D001323:Autoantibodies; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D013729:Terpenes; C540422:Aim2 protein, mouse; C530855:Sting1 protein, mouse; D000099197:STING Protein; C009042:pristane