Immune Netw.  2013 Dec;13(6):257-263. 10.4110/in.2013.13.6.257.

CP-690550 Treatment Ameliorates Established Disease and Provides Long-Term Therapeutic Effects in an SKG Arthritis Model

• Oh K
• Seo MW
• Kim IG
• Hwang YI
• Lee HY
• Lee DS

• KMID: 2150786
• DOI: http://doi.org/10.4110/in.2013.13.6.257

Abstract

Although pathogenesis of human rheumatoid arthritis (RA) remains unclear, arthritogenic T cells and downstream signaling mediators have been shown to play critical roles. An increasing numbers of therapeutic options have been added for the effective control of RA. Nevertheless, there is still a category of patients that fails treatment and suffers from progressive disease. The recently developed immunosuppressant CP-690550, a small molecule JAK kinase inhibitor, has been implicated as an important candidate treatment modality for autoimmune arthritis. In this study, we evaluated the therapeutic effect of CP-690550 on established arthritis using an SKG arthritis model, a pathophysiologically relevant animal model for human RA. CP-690550 treatment revealed remarkable long-term suppressive effects on SKG arthritis when administered to the well-advanced disease (clinical score 3.5~4.0). The treatment effect lasted at least 3 more weeks after cessation of drug infusion, and suppression of disease was correlated with the reduced pro-inflammatory cytokines, including IL-17, IFN-gamma, and IL-6 and increased level of immunoregulatory IL-10.

Keyword

Rheumatoid arthritis; CP-690550; SKG mice; IL-17; IL-10

MeSH Terms

Arthritis*
Arthritis, Rheumatoid
Cytokines
Humans
Interleukin-10
Interleukin-17
Interleukin-6
Models, Animal
Phosphotransferases
T-Lymphocytes
Cytokines
Interleukin-10
Interleukin-17
Interleukin-6
Phosphotransferases

Figure

• 

  Figure 1 Effects of CP-690550 on arthritis in SKG mice. SKG mice were intraperitoneally injected with curdlan. Osmotic pumps containing CP-690550 were implanted into the recipients at 14 days after curdlan injection. Data shown were obtained from a single experiment representative of 3 identical experiments; values are expressed as mean±SEM (5 mice per group).

• 

  Figure 2 CP-690550 reduced inflammatory cell infiltration and pathology in ankle joints of arthritis induced mice. At 48 days after arthritis induction, paws of the vehicle (A, B) or CP-690550 (C, D) treated mice were fixed in 4% paraformaldehyde, decalcified, and embedded in paraffin. Joint sections (5 mm) were prepared and stained with hematoxylin and eosin. These sections were examined under light microscopy (original magnification, ×100).

• 

  Figure 3 CP-690550 reduced IL-17 production in arthritis induced mice. Lymph nodes and spleens were harvested at 18 days post arthritis induction and were re-stimulated with PMA plus ionomycin followed by intracellular cytokine staining. Cells were analyzed using flowcytometer after staining with anti-CD4, anti-IL-17 and anti-IFN-γ antibodies. The data are representative of two independent determinations.

• 

  Figure 4 CP-690550 reduced transcription of pro-inflammatory cytokines, but increased transcription of IL-10. Total RNA was purified from joint tissue at day 18 post arthritis induction and mRNA expression was detected for IL-6, IL-10, IL-17 and IFN-γ by RT-PCR. The data are representative of two independent determinations (n=3 mice per group for each experiment).

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