Cartilage preservation by inhibition of Janus kinase 3 in two rodent models of rheumatoid arthritis

Milici, Anthony J.; Kudlacz, Elizabeth M.; Audoly, Laurent; Zwillich, Samuel H.; Changelian, Paul S.

doi:10.1186/ar2365

Cited by 145 publications

(114 citation statements)

References 42 publications

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“…The efficacy was dosage related with an efficacious dosage as low as 10 mg/kg once daily. Similar results were observed for CP-690,550 as previously reported in this model (34) (Figure 5B). Inflammation and damage to the paw were assessed microscopically.…”

Section: In Vitro Activity Wye-151650 (supporting

confidence: 92%

Selective functional inhibition of JAK‐3 is sufficient for efficacy in collagen‐induced arthritis in mice

Lin

Hegen

Quadros

et al. 2010

Arthritis & Rheumatism

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Objective. All ␥-chain cytokines signal through JAK-3 and JAK-1 acting in tandem. We undertook this study to determine whether the JAK-3 selective inhibitor WYE-151650 would be sufficient to disrupt cytokine signaling and to ameliorate autoimmune disease pathology without inhibiting other pathways mediated by JAK-1, JAK-2, and Tyk-2.Methods. JAK-3 kinase selective compounds were characterized by kinase assay and JAK-3-dependent (interleukin-2 [IL-2]) and -independent (IL-6, granulocyte-macrophage colony-stimulating factor [GM-CSF]) cell-based assays measuring proliferation or STAT phosphorylation. In vivo, off-target signaling was measured by IL-22-and erythropoietin (EPO)-mediated models, while on-target signaling was measured by IL-2-mediated signaling. Efficacy of JAK-3 inhibitors was determined using delayed-type hypersensitivity (DTH) and collagen-induced arthritis (CIA) models in mice.Results. In vitro, WYE-151650 potently suppressed IL-2-induced STAT-5 phosphorylation and cell proliferation, while exhibiting 10-29-fold less activity against JAK-3-independent IL-6-or GM-CSF-induced STAT phosphorylation. Ex vivo, WYE-151650 suppressed IL-2-induced STAT phosphorylation, but not IL-6-induced STAT phosphorylation, as measured in whole blood. In vivo, WYE-151650 inhibited JAK-3-mediated IL-2-induced interferon-␥ production and decreased the natural killer cell population in mice, while not affecting IL-22-induced serum amyloid A production or EPO-induced reticulocytosis. WYE-151650 was efficacious in mouse DTH and CIA models.Conclusion. In vitro, ex vivo, and in vivo assays demonstrate that WYE-151650 is efficacious in mouse CIA despite JAK-3 selectivity. These data question the need to broadly inhibit JAK-1-, JAK-2-, or Tyk-2-dependent cytokine pathways for efficacy.

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Section: In Vitro Activity Wye-151650 (supporting

confidence: 92%

Selective functional inhibition of JAK‐3 is sufficient for efficacy in collagen‐induced arthritis in mice

Lin

Hegen

Quadros

et al. 2010

Arthritis & Rheumatism

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“…Small-molecule inhibitors of JAKs are emerging as promising therapies for RA. Two compounds, tofacitinib (JAK1/2/3 inhibitor) and LY3009104 (JAK1/2 inhibitor), are undergoing late-stage clinical trials or nearing U.S. Food and Drug Administration approval for marketing (45,53,54). The combination of activities of SB1578 against JAK2, c-Fms, and FLT3, with selectivity for JAK2 within the JAK family, is unique.…”

Section: Discussionmentioning

confidence: 99%

SB1578, a Novel Inhibitor of JAK2, FLT3, and c-Fms for the Treatment of Rheumatoid Arthritis

Madan¹,

Goh²,

Hart³

et al. 2012

The Journal of Immunology

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SB1578 is a novel, orally bioavailable JAK2 inhibitor with specificity for JAK2 within the JAK family and also potent activity against FLT3 and c-Fms. These three tyrosine kinases play a pivotal role in activation of pathways that underlie the pathogenesis of rheumatoid arthritis. SB1578 blocks the activation of these kinases and their downstream signaling in pertinent cells, leading to inhibition of pathological cellular responses. The biochemical and cellular activities of SB1578 translate into its high efficacy in two rodent models of arthritis. SB1578 not only prevents the onset of arthritis but is also potent in treating established disease in collagen-induced arthritis mice with beneficial effects on histopathological parameters of bone resorption and cartilage damage. SB1578 abrogates the inflammatory response and prevents the infiltration of macrophages and neutrophils into affected joints. It also leads to inhibition of Ag-presenting dendritic cells and inhibits the autoimmune component of the disease. In summary, SB1578 has a unique kinase spectrum, and its pharmacological profile provides a strong rationale for the ongoing clinical development in autoimmune diseases.

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“…Tofacitinib (Selleck Chemicals, Houston, TX, USA) was dissolved in a sterile solution of PEG300, as used previously (18). Mice in the tofacitinib and vehicle treatment groups were anesthetized with isoflurane, and their dorsal surface was shaved 1 day prior to pump insertion.…”

Section: Methodsmentioning

confidence: 99%

“…The vehicle/controls used were poly (ethylene glycol) 300 (PEG300; Wako Pure Chemical Industries, Ltd.), rat immunoglobulin G (IgG) and human IgG (both from MP Biomedicals, LLC, Santa Ana, CA, USA) for tofacitinib, MR16-1 and etanercept, respectively. The dose of each treatment was determined as the effective dose reported on a collagen-induced arthritis model in previous studies (17)(18)(19).…”

Section: Methodsmentioning

confidence: 99%

“…Mice in the tofacitinib and vehicle treatment groups were anesthetized with isoflurane, and their dorsal surface was shaved 1 day prior to pump insertion. On day 0, a subcutaneous pocket was created under anesthesia with isoflurane, and an ALZET Mini-Osmotic Pump (model 2002, release rate 0.5 µl/h; Durect Co., Cupertino, CA, USA) was then inserted to deliver tofacitinib at a dosage of 15 mg/kg/day, or PEG300 as a control, as previously described (18).…”

Section: Methodsmentioning

confidence: 99%

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A cytokine signal inhibitor for rheumatoid arthritis enhances cancer metastasis via depletion of NK cells in an experimental lung metastasis mouse model of colon cancer

et al. 2017

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Abstract. Current therapy for rheumatoid arthritis (RA) relies on global suppression of the immune response or specific blockade of inflammatory cytokines. However, it is unclear how immunosuppressants affect patients with cancer. Therefore, in the present study, the effect of three biological agents, tofacitinib, anti-mouse IL-6 receptor antibody (MR16-1) and etanercept, which are used for the treatment of RA diseases, on a tumor-bearing mouse model was investigated. The effect of the three agents was examined using a mouse lung-metastasis model with the murine colon 26 cancer cell line. Lymphocyte subsets and natural killer (NK) cells in peripheral blood and spleen were analyzed using fluorescence-activated cell sorting, and the number of lung surface nodules was examined. In the continuous tofacitinib administration (15 mg/kg/day) group, the number of lung surface nodules was significantly increased compared with that of the vehicle-treated group (vehicle, 1.20±0.58; tofacitinib, 35.6±10.81; P<0.01). NK cell number in the blood and spleen of tofacitinib-treated mice was decreased 10-fold, and the percentage of cluster of differentiation (CD)11 + CD27 -NK cells was significantly reduced. MR16-1 [8 mg/mouse; once a week; intraperitoneal (i.p.)] or etanercept (1 mg/mouse; 3 times a week; i.p.) treatment did not affect the number of NK cells or lung metastasis. In the present study, immunosuppressants that target cytokines, including tofacitinib, were demonstrated to inhibit the proliferation and differentiation of NK cells, and exhibit the potential to promote cancer metastasis using a mouse model of lung metastasis. IntroductionImmune cells are associated with carcinogenesis, tumor growth, invasion and metastasis. Natural killer (NK) cells in particular serve an important role in immune surveillance, and are generally accepted as a beneficial cell population for anti-tumor immunity (1). Several studies have reported that depletion of NK cells causes increased survival of circulating tumor cells, resulting in enhanced cancer metastasis (2-5). In addition, it has been suggested that a favorable prognosis is associated with the extent of NK cell infiltration into the tumor in patients with gastric cancer or colorectal cancer (6,7). Therefore, inhibition of NK cell activity may promote cancer metastasis through a decrease in the number of NK cells.In addition, cluster of differentiation (CD)4 + and CD8 + T cells, which are specific for tumor-associated antigens, serve important roles in antitumor immunity (8,9). CD4 + T cells serve an important role in generating effective immune responses by stimulating CD8 + T cell proliferation and establishing long-lived functional T cell memory (8). It has been reported that CD4 + T cell can enhance CD8 + T cell recruitment and infiltration into tumors (8). Similarly, several reports have suggested that the infiltration of CD8 + T cells is associated with a better prognosis in colon cancer (10).Several inflammatory cytokines, including tumor necrosis factor (TNF)-α and interl...

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Cartilage preservation by inhibition of Janus kinase 3 in two rodent models of rheumatoid arthritis

Cited by 145 publications

References 42 publications

Selective functional inhibition of JAK‐3 is sufficient for efficacy in collagen‐induced arthritis in mice

Selective functional inhibition of JAK‐3 is sufficient for efficacy in collagen‐induced arthritis in mice

SB1578, a Novel Inhibitor of JAK2, FLT3, and c-Fms for the Treatment of Rheumatoid Arthritis

A cytokine signal inhibitor for rheumatoid arthritis enhances cancer metastasis via depletion of NK cells in an experimental lung metastasis mouse model of colon cancer

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