September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Cell adhesion factors drive angiogenesis and edema in treatment resistant Diabetic Retinopathy patients:evidence for alternate signaling
Author Affiliations & Notes
  • Priyanka Chevour
    GROW Laboratory, Narayana Nethralaya Foundation, Narayana Nethralaya, Bangalore, India
  • Santosh G K Gadde
    Vitreoretinal Service, Narayana Nethralaya, Bangalore, Karnataka, India
  • Naresh Kumar Yadav
    Vitreoretinal Service, Narayana Nethralaya, Bangalore, Karnataka, India
  • Swaminathan Sethu
    GROW Laboratory, Narayana Nethralaya Foundation, Narayana Nethralaya, Bangalore, India
  • Arkasubhra Ghosh
    GROW Laboratory, Narayana Nethralaya Foundation, Narayana Nethralaya, Bangalore, India
  • Footnotes
    Commercial Relationships   Priyanka Chevour, None; Santosh Gadde, None; Naresh Kumar Yadav, None; Swaminathan Sethu, None; Arkasubhra Ghosh, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 5439. doi:
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      Priyanka Chevour, Santosh G K Gadde, Naresh Kumar Yadav, Swaminathan Sethu, Arkasubhra Ghosh; Cell adhesion factors drive angiogenesis and edema in treatment resistant Diabetic Retinopathy patients:evidence for alternate signaling. Invest. Ophthalmol. Vis. Sci. 2016;57(12):5439.

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

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Abstract

Purpose : Determine the mechanisms underlying resistance to anti-angiogenic therapy in Diabetic Retinopathy (DR)/macular edema and uncover the molecular signaling networks driving them

Methods : Aqueous humor samples from 68 subjects undergoing intravitreal injections or cataract surgery were collected with written informed consent and approval of the Institutional Ethics Committee and classified as (i)Controls:cataract patients without DR(n=11) (ii)Controls Diabetes Mellitus:but no DR(n=7) (iii)Treatment naïve: samples taken at first intravitreal injection (n=9) (iv)Responders to intra-vitreal anti-VEGF treatment (n=9): decreasing macular edema 100μ after first injection (v) Non Responders to anti-VEGF treatment(n=13): minimum three intravitreal injections and persisting macular edema (vi)Vitreous Haemorrhage (n=19).
For the in vitro model, adult retinal pigment epithelial cells(ARPE-19) grown upto 70% confluency were treated with recombinant VEGF, bevacizumab, TNF, VEGF+bevacizumab and TNF+ bevacizumab. Quantification of secreted cytokines in aqueous humor of patients and culture media by cells ( post 24 hrs) was performed by flow cytometry.

Results : VEGF levels were comparable between the treatment responsive and resistant groups which were slightly elevated compared to the controls (p=0.453). However, in the treatment resistant group, soluble cell adhesion factors ICAM1 (p=0.002) and VCAM1(p=0.047) were significantly elevated compared to controls or treatment responsive group. We also observed significant elevation of IL8 and MCP1 in the treatment resistant group (p<0.05). The patient data was recapitulated in vitro wherein inflammatory stimuli (TNFα 10ng/ml) to ARPE-19 cells significantly elevated secretion of cell adhesion factors and cytokines apart from VEGF. Treatment with Bevacizumab reduced VEGF secretion from TNFα stimulated cells but could not rescue the elevated ICAM and inflammatory factors.

Conclusions : Our data identifies a VEGF-independent set of factors that drive neovascularization in the pathogenesis of DR and that regulate the patient’s response to anti-VEGF therapy to control associated macular edema. In vitro data illustrate that (ARPE-19 cells) undergoing inflammatory stress may utilise alternate signals to stimulate angiogenesis. These cell adhesion molecules may therefore serve as alternate treatment targets for anti-VEGF resistant patients

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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