A selective and potent CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases and delays graft rejection

Jenh, Chung‐Her; Cox, Mary Ann; Chen, Long; Reich, E.; Sullivan, Lee; Chen, Shu‐Cheng; Kinsley, David; Qian, Shixian; Kim, Seong Heon; Rosenblum, Stuart B.; Kozlowski, Joseph A.; Fine, Jay S.; Zavodny, Paul J.; Lundell, Daniel

doi:10.1186/1471-2172-13-2

Cited by 72 publications

(49 citation statements)

References 19 publications

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“…CXCL10 antibody treatment induced epidermal repigmentation in mice with established vitiligo, and therefore may offer a targeted systemic therapeutic option for patients with disease. A therapeutic strategy based on these observations may incorporate existing neutralizing antibodies or chemical inhibitors of IFNγ (51), CXCL10 (52), or CXCR3 (41, 53), or inhibitors of IFNγ or CXCL10 signaling through chemical inhibition or RNAi-induced knockdown. Completed clinical trials have tested either CXCL10 neutralization or CXCR3 blockade for psoriasis, Crohn’s disease, and ulcerative colitis, with disappointing results (41).…”

Section: Discussionmentioning

confidence: 99%

CXCL10 Is Critical for the Progression and Maintenance of Depigmentation in a Mouse Model of Vitiligo

et al. 2014

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Vitiligo is an autoimmune disease of the skin that results in disfiguring white spots. There are no FDA-approved treatments for vitiligo, and most off-label treatments yield unsatisfactory results. Vitiligo patients have increased numbers of autoreactive, melanocyte-specific CD8+ T cells in the skin and blood, which are directly responsible for melanocyte destruction. Here we report that gene expression in lesional skin from vitiligo patients reveals an IFN-γ-specific signature, including the chemokine CXCL10. CXCL10 is elevated in both vitiligo patient skin and serum and CXCR3, its receptor, is expressed on pathogenic T cells. To address the function of CXCL10 in vitiligo, we employed a mouse model of disease that also exhibits an IFN-γ-specific gene signature, expression of CXCL10 in the skin, and upregulation of CXCR3 on antigen-specific T cells. Mice that receive Cxcr3−/− T cells develop minimal depigmentation, as do mice lacking Cxcl10 or treated with CXCL10 neutralizing antibody. CXCL9 promotes autoreactive T cell global recruitment to the skin but not effector function while, in contrast, CXCL10 is required for effector function and localization within the skin. Surprisingly, CXCL10 neutralization in mice with established, widespread depigmentation induces reversal of disease, evidenced by repigmentation. These data identify a critical role for CXCL10 in both the progression and maintenance of vitiligo, and thereby support inhibiting CXCL10 as a targeted treatment strategy.

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Section: Discussionmentioning

confidence: 99%

CXCL10 Is Critical for the Progression and Maintenance of Depigmentation in a Mouse Model of Vitiligo

et al. 2014

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“…The selective CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases. 46 The CXCR3 antagonist AMG 487 exhibits inhibitory effects on lung metastasis in breast cancer. 47 In the present study, we demonstrated that JN-2 inhibits osteolytic bone metastasis of 4T1 cells with a decrease in tumor outgrowth, P65 expression, osteoclast formation, and the expression of RANKL and CXCL10.…”

Section: Discussionmentioning

confidence: 99%

NF-κB signaling regulates cell-autonomous regulation of CXCL10 in breast cancer 4T1 cells

Jin

Kim

et al. 2017

Exp Mol Med

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The chemokine CXCL10 and its receptor CXCR3 play a role in breast cancer metastasis to bone and osteoclast activation. However, the mechanism of CXCL10/CXCR3-induced intracellular signaling has not been fully investigated. To evaluate CXCL10-induced cellular events in the mouse breast cancer cell line 4T1, we developed a new synthetic CXCR3 antagonist JN-2. In this study, we observed that secretion of CXCL10 in the supernatant of 4T1 cells was gradually increased during cell growth. JN-2 inhibited basal and CXCL10-induced CXCL10 expression and cell motility in 4T1 cells. Treatment of 4T1 cells with CXCL10 increased the expression of P65, a subunit of the NF-κB pathway, via activation of the NF-κB transcriptional activity. Ectopic overexpression of P65 increased CXCL10 secretion and blunted JN-2-induced suppression of CXCL10 secretion, whereas overexpression of IκBα suppressed CXCL10 secretion. These results indicate that the CXCL10/CXCR3 axis creates a positive feedback loop through the canonical NF-κB signaling pathway in 4T1 cells. In addition, treatment of osteoblasts with conditioned medium from JN-2-treated 4T1 cells inhibited the expression of RANKL, a crucial cytokine for osteoclast differentiation, which resulted in an inhibitory effect on osteoclast differentiation in the co-culture system of bone marrow-derived macrophages and osteoblasts. Direct intrafemoral injection of 4T1 cells induced severe bone destruction; however, this effect was suppressed by the CXCR3 antagonist via downregulation of P65 expression in an animal model. Collectively, these results suggest that the CXCL10/CXCR3-mediated NF-κB signaling pathway plays a role in the control of autonomous regulation of CXCL10 and malignant tumor properties in breast cancer 4T1 cells.

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“…Small molecule CXCR3 antagonists could overcome some of these challenges, and have shown efficacy in reducing inflammation in the collagen-induced arthritis (CIA) and experimental autoimmune encephalomyelitis (EAE) models, as well as prolonged allograft survival (46). Topical delivery of a selective CXCR3 antagonist could provide an improved therapeutic index, by limiting systemic exposure to immuomodulatory agents.…”

Section: Discussionmentioning

confidence: 99%

CXCR3 Blockade Inhibits T Cell Migration into the Skin and Prevents Development of Alopecia Areata

Dai¹,

Xing²,

Cerise³

et al. 2016

The Journal of Immunology

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Alopecia areata (AA) is an autoimmune disease of the hair follicle (HF) that results in hair loss of varying severity. Recently, we showed that IFN-γ-producing NKG2D+CD8+ T cells actively infiltrate the HF, and are responsible for its destruction in C3H/HeJ AA mice. Our transcriptional profiling of human and mouse alopecic skin showed that the IFN pathway is the dominant signaling pathway involved in AA. We showed that IFN inducible chemokines (CXCL9/10/11) are markedly upregulated in the skin of AA lesions, and further, that the IFN inducible chemokine receptor, CXCR3, is upregulated on alopecic effector T cells. To demonstrate whether CXCL9/10/11 chemokines were required for development of AA, we treated mice with blocking antibodies to CXCR3, which prevented the development of AA in the graft model, inhibiting the accumulation of NKG2D+CD8+ T cells in the skin and cutaneous lymph nodes. These data demonstrate proof of concept that interfering with the Tc1 response in AA via blockade of IFN inducible chemokines can prevent the onset of AA. CXCR3 blockade could be approached clinically in human AA with either biologic or small molecule inhibition, the latter being particularly intriguing as a topical therapeutic.

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A selective and potent CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases and delays graft rejection

Cited by 72 publications

References 19 publications

CXCL10 Is Critical for the Progression and Maintenance of Depigmentation in a Mouse Model of Vitiligo

CXCL10 Is Critical for the Progression and Maintenance of Depigmentation in a Mouse Model of Vitiligo

NF-κB signaling regulates cell-autonomous regulation of CXCL10 in breast cancer 4T1 cells

CXCR3 Blockade Inhibits T Cell Migration into the Skin and Prevents Development of Alopecia Areata

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