June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
Evaluation of JAK inhibition with topical tofacitinib in an experimental autoimmune uveitis model (EAU)
Author Affiliations & Notes
  • Jing-Feng Huang
    La Jolla BioConsulting, San Diego, CA
  • Yi Zhang
    bioTheranostics, Inc.,, San Diego, CA
  • Brad Hirakawa
    Pfizer Inc., San Diego, CA
  • Footnotes
    Commercial Relationships Jing-Feng Huang, Pfizer Inc. (E); Yi Zhang, None; Brad Hirakawa, Pfizer (E)
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 2536. doi:
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      Jing-Feng Huang, Yi Zhang, Brad Hirakawa; Evaluation of JAK inhibition with topical tofacitinib in an experimental autoimmune uveitis model (EAU). Invest. Ophthalmol. Vis. Sci. 2013;54(15):2536.

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

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Abstract

Purpose: To evaluate the therapeutic efficacy of topical Janus kinase (JAK) inhibitor, tofacitinib, in intraocular inflammation in EAU.

Methods: Albino Lewis rats were randomly divided into four groups (N=15 each) on Day 1, before injected in the footpad with S-Antigen (100 μg in 100 μL) in Freud’s complete adjuvant to induce EAU. From Day 7 to the end of the study (Day 16), animals were treated with either one of the four: no treatment, systemic cyclosporine A (CsA, 20 mg/kg) once per day, topical tofacitinib (0.03%) three times per day (3x) or once per day (1x). Severity of inflammation was evaluated with a slit-lamp every two days from Day 10 to Day 16. On Day16, eyeballs from 10 animals were prepared for histological evaluation (retinal thickness and cell infiltration). From the rest of 5 animals in each group, vitreous fluid were collected for analysis of 27 cytokine and chemokine; and iris-ciliary body (ICB) and retina/choroid were collected for gene expression analysis.

Results: Treatment of EAU during the efferent phase with topical tofacitinib at three times a day (3x) significantly reduced intraocular inflammation as determined in clinical analyses (mean score on Day 16 was 1.7 ± 2.4 compared with 3.2 ± 1.8 in the non-treated group, P=0.0235), and consistent with that, tofacitinib (3X) reduced the inflammatory cell infiltration and the retinal lesions, as revealed by histology analyses (mean clinical score on Day 16 was 2.6 ± 3.0 compared with 3.7 ± 2.9 in the non-treated group). No significant effect was observed in tofacitinib (1x) group, while systemic administration of CsA completely blocked intraocular inflammation in EAU. Compared with non-treated group, tofacitinib (3x) group had significantly lower level of inflammatory chemokine (TNFalpha, lymphotactin, CCL-2, CCL-5 and CXCL-10) in the vitreous, and markedly lower gene expression level of inflammatory chemokine, immune mediators and receptors (CCL-2, CCL-5, CXCL-10, S100A8, CCR5 and IL-2Recptor gamma) in both ICB and retina/choroid (P < 0.05).

Conclusions: JAK inhibition with topical tofacitinib three times a day reduced intraocular inflammation in autoimmune uveitis. It markedly suppressed the expression of many inflammatory chemokine and chemokine receptors in ocular tissues, and reduced infiltration of immune cells and subsequent tissue damage.

Keywords: 746 uveitis-clinical/animal model • 555 immunomodulation/immunoregulation • 432 autoimmune disease  
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