April 2010
Volume 51, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2010
Autoimmune Retinal Inflammation is Suppressed by a Novel Polymeric Anti-Angiogenic Drug
Author Affiliations & Notes
  • T. Yoshimura
    Vascular Biology Program, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts
  • O. Benny
    Vascular Biology Program, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts
  • L. Bazinet
    Vascular Biology Program, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts
  • R. J. D'Amato
    Vascular Biology Program, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts
  • Footnotes
    Commercial Relationships  T. Yoshimura, None; O. Benny, WO 2009003110 20081231, P; L. Bazinet, None; R.J. D'Amato, None.
  • Footnotes
    Support  Internal, departmental fund
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 817. doi:
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    • Get Citation

      T. Yoshimura, O. Benny, L. Bazinet, R. J. D'Amato; Autoimmune Retinal Inflammation is Suppressed by a Novel Polymeric Anti-Angiogenic Drug. Invest. Ophthalmol. Vis. Sci. 2010;51(13):817.

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

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Abstract

Purpose: : Retinal inflammation caused by non-infectious, autoimmune uveitis is one of the major causes of blindness. Lodamin, a polymeric conjugation of TNP-470 and a potent broad-spectrum anti-angiogenic drug, has been shown to inhibit angiogenesis and tumor growth by oral administration without adverse side effects. In this study, we show for the first time the anti-inflammatory effect of Lodamin on T cell proliferation/differentiation. These effects are demonstrated in a model of autoimmune retinal inflammation.

Methods: : Lodamin was prepared by chemical conjugation of polyethylene glycol-polylactic acid (PEG-PLA) to TNP-470. Carboxyfluorescein succinimidyl ester (CFSE)-labeled splenocytes from C57BL/6 mice were activated with αCD3 Ab in the presence of vehicle or Lodamin. Proliferation of CD4+ T cells was measured by CFSE dilution. CD4+ T cells were differentiated into Th1 (IL-12 and αIL-4 Ab) and Th17 (TGF-β1, IL-6, and αIFN-γ/αIL-4 Ab) in the presence of vehicle or Lodamin. Expansion of Th1/Th17 cells was evaluated by intracellular cytokine staining. Experimental autoimmune uveitis (EAU) was induced by immunizing C57BL/6 mice with human interphotoreceptor retinoid-binding protein (IRBP) 1-20. Lodamin at a dose of 30mg/kg, or vehicle was orally administrated every other day after immunization. EAU severity was evaluated clinically and histopathologically on day 21. Draining lymph node cells were harvested and IRBP-specific IFN-γ/IL-17 production was analyzed by ELISA. mRNA from retinas was isolated for quantitative real-time PCR (qPCR).

Results: : Lodamin suppressed αCD3-mediated CD4+ T cell proliferation and importantly, both Th1/Th17 differentiation. Oral treatment of Lodamin significantly suppressed IRBP-specific IFN-γ/IL-17 production and EAU progression both clinically and histopathologically. Furthermore, qPCR analysis revealed that Lodamin attenuated intraocular expression of major inflammatory cytokines such as IFN-γ, IL-17, and IL-6.

Conclusions: : The results show that Lodamin significantly suppresses T cell proliferation, Th1/Th17 differentiation, IRBP-specific Th1/Th17 responses and disease severity in EAU. We conclude that oral treatment with Lodamin holds promise for the treatment of retinal inflammatory diseases.

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