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Inhibition of TNF-alpha-induced sickle RBC retention in retina by a VLA-4 antagonist.
Invest Ophthalmol Vis Sci 2001; 42(6):1349-55IO

Abstract

PURPOSE

Patients with sickle cell disease have elevated circulating levels of cytokines including tumor necrosis factor (TNF) alpha. TNF-alpha stimulates expression by endothelial cells of adhesion molecules, including vascular cell adhesion molecule (VCAM) 1. Others have demonstrated that VLA-4 (alpha(4)beta(1)), 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-alpha increases retention of sickle erythrocytes in retina and if that retention can be inhibited.

METHODS

TNF-alpha 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-alpha 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 alpha(4)beta(1) and alpha(4)beta(7), or a monoclonal antibody against VLA-4 (19H8), significantly inhibited the TNF-alpha-induced retention (P < or = 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 TNF-alpha 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.

Authors+Show Affiliations

Wilmer Ophthalmological Institute, Johns Hopkins Hospital, 170 Woods Research Building, 600 N. Wolfe Street, Baltimore, MD 21287-9115, USA. glutty@jhmi.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11328750

Citation

Lutty, G A., et al. "Inhibition of TNF-alpha-induced Sickle RBC Retention in Retina By a VLA-4 Antagonist." Investigative Ophthalmology & Visual Science, vol. 42, no. 6, 2001, pp. 1349-55.
Lutty GA, Taomoto M, Cao J, et al. Inhibition of TNF-alpha-induced sickle RBC retention in retina by a VLA-4 antagonist. Invest Ophthalmol Vis Sci. 2001;42(6):1349-55.
Lutty, G. A., Taomoto, M., Cao, J., McLeod, D. S., Vanderslice, P., McIntyre, B. W., ... Nagel, R. L. (2001). Inhibition of TNF-alpha-induced sickle RBC retention in retina by a VLA-4 antagonist. Investigative Ophthalmology & Visual Science, 42(6), pp. 1349-55.
Lutty GA, et al. Inhibition of TNF-alpha-induced Sickle RBC Retention in Retina By a VLA-4 Antagonist. Invest Ophthalmol Vis Sci. 2001;42(6):1349-55. PubMed PMID: 11328750.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of TNF-alpha-induced sickle RBC retention in retina by a VLA-4 antagonist. AU - Lutty,G A, AU - Taomoto,M, AU - Cao,J, AU - McLeod,D S, AU - Vanderslice,P, AU - McIntyre,B W, AU - Fabry,M E, AU - Nagel,R L, PY - 2001/5/1/pubmed PY - 2001/5/22/medline PY - 2001/5/1/entrez SP - 1349 EP - 55 JF - Investigative ophthalmology & visual science JO - Invest. Ophthalmol. Vis. Sci. VL - 42 IS - 6 N2 - PURPOSE: Patients with sickle cell disease have elevated circulating levels of cytokines including tumor necrosis factor (TNF) alpha. TNF-alpha stimulates expression by endothelial cells of adhesion molecules, including vascular cell adhesion molecule (VCAM) 1. Others have demonstrated that VLA-4 (alpha(4)beta(1)), 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-alpha increases retention of sickle erythrocytes in retina and if that retention can be inhibited. METHODS: TNF-alpha 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-alpha 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 alpha(4)beta(1) and alpha(4)beta(7), or a monoclonal antibody against VLA-4 (19H8), significantly inhibited the TNF-alpha-induced retention (P < or = 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 TNF-alpha 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. SN - 0146-0404 UR - https://www.unboundmedicine.com/medline/citation/11328750/Inhibition_of_TNF_alpha_induced_sickle_RBC_retention_in_retina_by_a_VLA_4_antagonist_ DB - PRIME DP - Unbound Medicine ER -