Blockade of the interleukin-21/interleukin-21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis

Authors

  • Deborah A. Young,

    Corresponding author
    1. Wyeth Research, Cambridge, Massachusetts
    • Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140
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  • Martin Hegen,

    1. Wyeth Research, Cambridge, Massachusetts
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  • Hak Ling Margery Ma,

    1. Wyeth Research, Cambridge, Massachusetts
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  • Matthew J. Whitters,

    1. Wyeth Research, Cambridge, Massachusetts
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  • Leo M. Albert,

    1. Wyeth Research, Cambridge, Massachusetts
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  • Leslie Lowe,

    1. Wyeth Research, Cambridge, Massachusetts
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  • Mayra Senices,

    1. Wyeth Research, Cambridge, Massachusetts
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  • Paul W. Wu,

    1. Wyeth Research, Cambridge, Massachusetts
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  • Barbara Sibley,

    1. Wyeth Research, Cambridge, Massachusetts
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  • Yelena Leathurby,

    1. Wyeth Research, Cambridge, Massachusetts
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  • Tom P. Brown,

    1. Wyeth Research, Andover, Massachusetts
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  • Cheryl Nickerson-Nutter,

    1. Wyeth Research, Cambridge, Massachusetts
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    • Drs. Young, Hegen, and Ma, Mr. Whitters, Mr. Albert, Ms Lowe, Ms Senices, Mr. Wu, Ms Sibley, and Drs. Nickerson-Nutter, Keith, and Collins hold stock options in Wyeth.

  • James C. Keith Jr.,

    1. Wyeth Research, Cambridge, Massachusetts
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  • Mary Collins

    1. Wyeth Research, Cambridge, Massachusetts
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Abstract

Objective

Interleukin-21 (IL-21) is a T cell–derived cytokine that modulates T cell, B cell, and natural killer cell responses. In this study, the effects of blocking IL-21 were examined in 2 rodent models of rheumatoid arthritis (RA) to determine whether IL-21 contributes to their pathologic processes.

Methods

DBA/1 mice were immunized with bovine type II collagen and then treated with murine IL-21 receptor Fc fusion protein (IL-21R.Fc), which was initiated after the onset of arthritis symptoms in 10% of the cohort. The mice were assessed 3 times per week for signs of disease, including histologic features as well as serum cytokine, Ig, and cytokine messenger RNA (mRNA) levels in the paws. In a separate experiment, Lewis rats were immunized with Freund's complete adjuvant followed by administration of IL-21R.Fc at the peak of inflammation in the joints. Rats were assessed daily for histologic features and for scoring of arthritis severity. In addition, the effects of IL-21R.Fc on the production of interferon-γ (IFNγ) by T cells were examined.

Results

Treatment of DBA/1 mice with IL-21R.Fc reduced the clinical and histologic signs of collagen-induced arthritis. Nonspecific IgG1 levels were decreased in response to treatment. The levels of IL-6 mRNA in the paws and the serum IL-6 levels were decreased after treatment with IL-21R.Fc. IFNγ mRNA levels were increased in the paws, and the addition of IL-21R.Fc to collagen-activated lymph node cultures enhanced the levels of IFNγ. Collagen-specific spleen cell responses in IL-21R.Fc–treated mice were observed as reduced levels of IFNγ and increased levels of IL-6. Treatment of Lewis rats with IL-21R.Fc after induction of adjuvant-induced arthritis resulted in reversal of disease signs and improvements in histologic parameters.

Conclusion

These findings demonstrate a pathogenic role for IL-21 in animal models of RA, and support consideration of IL-21 as a therapeutic target in human RA.

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