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

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-gamma (IFNgamma) 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. IFNgamma mRNA levels were increased in the paws, and the addition of IL-21R.Fc to collagen-activated lymph node cultures enhanced the levels of IFNgamma. Collagen-specific spleen cell responses in IL-21R.Fc-treated mice were observed as reduced levels of IFNgamma 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.

• Authors: Deborah A Young, Martin Hegen, Hak Ling Margery Ma, Matthew J Whitters, Leo M Albert, Leslie Lowe, Mayra Senices, Paul W Wu, Barbara Sibley, Yelena Leathurby, Tom P Brown, Cheryl Nickerson-Nutter, James C Keith Jr, Mary Collins
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 56 Issue 4 Pg. 1152-63 (Apr 2007) ISSN: 0004-3591 [Print] United States
• PMID: 17393408 (Publication Type: Journal Article)

Chemical References

• Cytokines
• Il21r protein, mouse
• Immunoglobulin Fc Fragments
• Interleukin-21 Receptor alpha Subunit
• Interleukins
• RNA, Messenger
• Receptors, Interleukin-21
• Receptors, Tumor Necrosis Factor
• Recombinant Fusion Proteins
• interleukin-21

Topics

• Animals
• Arthritis, Experimental (metabolism, pathology, prevention & control)
• Cells, Cultured
• Cytokines (blood, genetics)
• Dose-Response Relationship, Drug
• Gene Expression
• Immunoglobulin Fc Fragments (administration & dosage)
• Interleukin-21 Receptor alpha Subunit (administration & dosage, metabolism)
• Interleukins (antagonists & inhibitors, metabolism)
• Lymph Nodes (drug effects, metabolism)
• Lymphocyte Activation
• Male
• Mice
• Mice, Inbred DBA
• RNA, Messenger (metabolism)
• Rats
• Rats, Inbred Lew
• Rats, Sprague-Dawley
• Receptors, Interleukin-21 (antagonists & inhibitors, metabolism)
• Receptors, Tumor Necrosis Factor (administration & dosage, antagonists & inhibitors, genetics)
• Recombinant Fusion Proteins (administration & dosage)
• Spleen (drug effects, metabolism)
• T-Lymphocytes (drug effects, metabolism)