July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Non-redundant requirement for CXCR3 signaling for effective treatment of eye-specific autoimmunity with type I IFNs
Author Affiliations & Notes
  • Jun Chen
    State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangzhou, China
  • Chunmei Li
    State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangzhou, China
  • Weiwei Wang
    State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangzhou, China
  • Zilin Chen
    State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangzhou, China
  • Ying Chen
    State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangzhou, China
  • Hongyan Zhou
    State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangzhou, China
  • Wai Po Chong
    State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangzhou, China
  • Igal Gery
    NEI/NIH, Bethesda, Maryland, United States
  • Rachel R Caspi
    NEI/NIH, Bethesda, Maryland, United States
  • Footnotes
    Commercial Relationships   Jun Chen, None; Chunmei Li, None; Weiwei Wang, None; Zilin Chen, None; Ying Chen, None; Hongyan Zhou, None; Wai Po Chong, None; Igal Gery, None; Rachel Caspi, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 2537. doi:https://doi.org/
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Jun Chen, Chunmei Li, Weiwei Wang, Zilin Chen, Ying Chen, Hongyan Zhou, Wai Po Chong, Igal Gery, Rachel R Caspi; Non-redundant requirement for CXCR3 signaling for effective treatment of eye-specific autoimmunity with type I IFNs. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2537. doi: https://doi.org/.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
Abstract

Purpose : Type I interferons (IFNs) have shown therapeutic potential in treating central nervous system (CNS) autoimmune diseases, e.g. IFN-β for multiple sclerosis and IFN-α for uveitis. However, treatment is not always effective in patients, and the molecular mechanisms by which type I IFNs exert their immunomodulatory functions remain largely unknown.

Methods : To address this question we examined the modulatory effects of type I IFNs in mouse models of experimental autoimmune uveitis (EAU) and T cell-transfer model of experimental uveitis (Chen et al. J Immunol 2006), as well as in PBMCs of patients with autoimmune uveitis. Autopathogenic T cells were detected and tracked in mice with a clonotypic antibody.

Results : Effective treatment with type I IFNs inhibited autopathogenic CD4+ T cell migration to effector sites in mice by upregulating expression of the cognate ligands CXCL9, CXCL10 and CXCL11, causing ligand-mediated downregulation of CXCR3 expression and effector T cell retention in the spleen. These effects of type I IFNs also required IFN-γ. In the absence of CXCR3, type I IFNs were ineffective in active EAU. In patients with uveitis, disease exacerbations correlated with reduced serum IFN-α concentrations. Importantly, type I IFNs inhibited CXCR3 expression and human effector T cell migration, and these parameters markedly correlated with IFN-α therapeutic efficacy in uveitis patients.

Conclusions : We demonstrate a non-redundant requirement for GαI-coupled CXCR3 in the immunomodulatory actions of type I IFNs that culminates in the suppression of human uveitis and EAU. Our findings provide new insights into the molecular basis of type I IFN therapy for CNS autoimmune diseases and identify CXCR3 as a critical biomarker for effective immunotherapy with type I IFNs.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×