Characterization of the KRN cell transfer model of rheumatoid arthritis (KRN-CTM), a chronic yet synchronized version of the K/BxN mouse.
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.
LaBranche
Timothy P
TP
Global Research & Development, Pfizer Inc., Chesterfield, Missouri, USA. timothy.labranche@pfizer.com
Hickman-Brecks
Cynthia L
CL
Meyer
Debra M
DM
Storer
Chad E
CE
Jesson
Michael I
MI
Shevlin
Kimberly M
KM
Happa
Fernando A
FA
Barve
Ruteja A
RA
Weiss
David J
DJ
Minnerly
John C
JC
Racz
Jennifer L
JL
Allen
Paul M
PM
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*