A highly selective, orally active inhibitor of Janus kinase 2, CEP-33779, ablates disease in two mouse models of rheumatoid arthritisReportar como inadecuado




A highly selective, orally active inhibitor of Janus kinase 2, CEP-33779, ablates disease in two mouse models of rheumatoid arthritis - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Arthritis Research and Therapy

, 13:R68

First Online: 21 April 2011Received: 31 August 2010Revised: 10 March 2011Accepted: 21 April 2011

Abstract

IntroductionJanus kinase 2 JAK2 is involved in the downstream activation of signal transducer and activator of transcription 3 STAT3 and STAT5 and is responsible for transducing signals for several proinflammatory cytokines involved in the pathogenesis of rheumatoid arthritis RA, including interleukin IL-6, interferon γ IFNγ and IL-12. In this paper, we describe the efficacy profile of CEP-33779, a highly selective, orally active, small-molecule inhibitor of JAK2 evaluated in two mouse models of RA.

MethodsCollagen antibody-induced arthritis CAIA and collagen type II CII-induced arthritis CIA were established before the oral administration of a small-molecule JAK2 inhibitor, CEP-33779, twice daily at 10 mg-kg, 30 mg-kg, 55 mg-kg or 100 mg-kg over a period of 4 to 8 weeks.

ResultsPharmacodynamic inhibition of JAK2 reduced mean paw edema and clinical scores in both CIA and CAIA models of arthritis. Reduction in paw cytokines IL-12, IFNγ and tumor necrosis factor α and serum cytokines IL-12 and IL-2 correlated with reduced spleen CII-specific T helper 1 cell frequencies as measured by ex vivo IFNγ enzyme-linked immunosorbent spot assay. Both models demonstrated histological evidence of disease amelioration upon treatment for example, reduced matrix erosion, subchondral osteolysis, pannus formation and synovial inflammation and reduced paw phosphorylated STAT3 levels. No changes in body weight or serum anti-CII autoantibody titers were observed in either RA model.

ConclusionsThis study demonstrates the utility of using a potent and highly selective, orally bioavailable JAK2 inhibitor for the treatment of RA. Using a selective inhibitor of JAK2 rather than pan-JAK inhibitors avoids the potential complication of immunosuppression while targeting critical signaling pathways involved in autoimmune disease progression.

AbbreviationsCIItype II collagen

CAIAcollagen antibody-induced arthritis

CIAcollagen-induced arthritis

RArheumatoid arthritis

RTroom temperature.

Electronic supplementary materialThe online version of this article doi:10.1186-ar3329 contains supplementary material, which is available to authorized users.

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Autor: Kristine L Stump - Lily D Lu - Pawel Dobrzanski - Cynthia Serdikoff - Diane E Gingrich - Ben J Dugan - Thelma S Angele

Fuente: https://link.springer.com/







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