Inhibition of TNF-α-induced sickle RBC retention in retina by a VLA-4 antagonist

G. A. Lutty, M. Taomoto, J. Cao, D. S. McLeod, P. Vanderslice, B. W. McIntyre, M. E. Fabry, R. L. Nagel

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose. Patients with sickle cell disease have elevated circulating levels of cytokines including tumor necrosis factor (TNF) α. TNF-α stimulates expression by endothelial cells of adhesion molecules, including vascular cell adhesion molecule (VCAM) 1. Others have demonstrated that VLA-4 (α4β1), a ligand for VCAM-1 or fibronectin, is present on a fraction of sickle reticulocytes. The intent of this study was to determine, using a rat model, if TNF-α increases retention of sickle erythrocytes in retina and if that retention can be inhibited. Methods. TNF-α was given intraperitoneally to rats 5 hours before IV administration of FITC-labeled, density-separated sickle erythrocytes. After 5 minutes, rats were exsanguinated, and retinas were excised and incubated for ADPase activity, permitting the determination of the number and location of retained cells. Results. TNF-α caused a three- to fourfold increase in retention of sickle erythrocytes in retinal capillaries (P < 0.05) but not of normal human erythrocytes. Preincubation of sickle erythrocytes with TBC772, a peptide that blocks the binding of α4β1 and α4β7, or a monoclonal antibody against VLA-4 (19H8), significantly inhibited the TNF-α-induced retention (P ≤ 0.02), whereas a control cyclic peptide and antibody had no effect. IV TBC772 also inhibited sickle erythrocyte retention (P = 0.01). Two intravenously administered anti-fibronectin antibodies inhibited sickle cell retention as well, but an anti-rat VCAM-1 antibody did not inhibit retention. Conclusions. The authors conclude that TNT-α stimulates retention of sickle erythrocytes in the retinal vasculature. This increased retention can be blocked by a VLA-4 antagonist, suggesting that the cells retained after cytokine stimulation are reticulocytes. The counter-receptor for VLA-4 in this rat retina model appears to be fibronectin and not VCAM-1, based on data obtained using antibodies against these molecules.

Original languageEnglish (US)
Pages (from-to)1349-1355
Number of pages7
JournalInvestigative Ophthalmology and Visual Science
Volume42
Issue number6
StatePublished - 2001

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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