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


CONCLUSIONS
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.
Young
Deborah A
DA
Wyeth Research, Cambridge, Massachusetts 02140, USA. dyoung@wyeth.com
Hegen
Martin
M
Ma
Hak Ling Margery
HL
Whitters
Matthew J
MJ
Albert
Leo M
LM
Lowe
Leslie
L
Senices
Mayra
M
Wu
Paul W
PW
Sibley
Barbara
B
Leathurby
Yelena
Y
Brown
Tom P
TP
Nickerson-Nutter
Cheryl
C
Keith
James C
JC
Collins
Mary
M
D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage*; D053738:Interleukin-21 Receptor alpha Subunit / Q000008:administration & dosage* / Q000378:metabolism; D007378:Interleukins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008198:Lymph Nodes / Q000187:drug effects / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D053655:Receptors, Interleukin-21 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage*; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D000098546:Interleukin-21
D016207:Cytokines; C508118:Il21r protein, mouse; D007141:Immunoglobulin Fc Fragments; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins; D012333:RNA, Messenger; D053655:Receptors, Interleukin-21; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D000098546:Interleukin-21