title: Characterization of the KRN cell transfer model of rheumatoid arthritis (KRN-CTM), a chronic yet synchronized version of the K/BxN mouse.
abstract: In this study, a chronic yet synchronized version of the K/BxN mouse, the KRN-cell transfer model (KRN-CTM), was developed and extensively characterized. The transfer of purified splenic KRN T cells into T cell-deficient B6.TCR.Calpha(-/-)H-2(b/g7) mice induced anti-glucose 6-phosphate isomerase antibody-dependent chronic arthritis in 100% of the mice with uniform onset of disease 7 days after T cell transfer. Cellular infiltrations were assessed by whole-ankle transcript microarray, cytokine and chemokine levels, and microscopic and immunohistochemical analyses 7 through 42 days after T cell transfer. Transcripts identified an influx of monocytes/macrophages and neutrophils into the ankles and identified temporal progression of cartilage damage and bone resorption. In both serum and ankle tissue there was a significant elevation in interleukin-6, whereas macrophage inflammatory protein-1 alpha and monocyte chemotactic protein-1 were only elevated in tissue. Microscopic and immunohistochemical analyses revealed a time course for edema, synovial hypertrophy and hyperplasia, infiltration of F4/80-positive monocytes/macrophages and myeloperoxidase-positive neutrophils, destruction of articular cartilage, pannus invasion, bone resorption, extra-articular fibroplasia, and joint ankylosis. The KRN cell transfer model replicates many features of chronic rheumatoid arthritis in humans in a synchronized manner and lends itself to manipulation of adoptively transferred T cells and characterizing specific genes and T cell subsets responsible for rheumatoid arthritis pathogenesis and progression.
authors.affiliation: Global Research & Development, Pfizer Inc., Chesterfield, Missouri, USA. timothy.labranche@pfizer.com
authors.forename: Timothy P
authors.initials: TP
authors.lastname: LaBranche
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Hickman-Brecks
authors.forename: Debra M
authors.initials: DM
authors.lastname: Meyer
authors.forename: Chad E
authors.initials: CE
authors.lastname: Storer
authors.forename: Michael I
authors.initials: MI
authors.lastname: Jesson
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Shevlin
authors.forename: Fernando A
authors.initials: FA
authors.lastname: Happa
authors.forename: Ruteja A
authors.initials: RA
authors.lastname: Barve
authors.forename: David J
authors.initials: DJ
authors.lastname: Weiss
authors.forename: John C
authors.initials: JC
authors.lastname: Minnerly
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Racz
authors.forename: Paul M
authors.initials: PM
authors.lastname: Allen
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007249:Inflammation; D007596:Joints / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology* / Q000637:transplantation*