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.

Th17 cells can provide B cell help in autoantibody induced arthritis.

K/BxN mice develop a spontaneous destructive arthritis driven by T cell dependent anti-glucose-6-phosphate isomerase (GPI) antibody production. In this study, a modified version of the K/BxN model, the KRN-cell transfer model (KRN-CTM), was established to determine the contribution of Th17 cells in the development of chronic arthritis. The transfer of naive KRN T cells into B6.TCR.Cα(-/-)H-2(b/g7) T cell deficient mice induced arthritis by day 10 of transfer. Arthritis progressively developed for a period of up to 14 days following T cell transfer, thereafter the disease severity declined, but did not resolve. Both IL-17A and IFNγ were detected in the recovered T cells from the popliteal lymph nodes and ankles. The transfer of KRN Th17 polarized KRN CD4(+) T cells expressing IL-17A and IFNγ induced arthritis in all B6.TCR.Cα(-/-)H-2(b/g7) mice however the transfer of Th1 polarized KRN CD4(+) T cells expressing IFNγ alone induced disease in only 2/3 of the mice and disease induction was delayed compared to Th17 transfers. Th17 polarized KRN/T-bet(-/-) cells induced arthritis in all mice and surprisingly, IFNγ was produced demonstrating that T-bet expression is not critical for arthritis induction, regardless of the cytokine expression. Neutralization of IFNγ in KRN Th17 transfers resulted in earlier onset of disease while the neutralization of IL-17A delayed disease development. Consistent with K/BxN mice, naive KRN T cell transfers and Th17 polarized KRN/T-bet(-/-) transfers induced anti-GPI IgG(1) dominant responses while KRN Th17 cells induced high levels of IgG(2b). These data demonstrate that Th17 cells can participate in the production of autoantibodies that can induce arthritis.