HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lutty, G. A. Articles by Nagel, R. L. Search for Related Content PubMed PubMed Citation Articles by Lutty, G. A. Articles by Nagel, R. L.

Inhibition of TNF-–induced Sickle RBC Retention in Retina by a VLA-4 Antagonist

¹ From the Wilmer Ophthalmological Institute, Johns Hopkins Hospital, Baltimore, Maryland; ² Texas Biotechnology Corp., Houston, Texas; ³ Department of Immunology, University of Texas, Houston; and ⁴ Division of Hematology, Albert Einstein College of Medicine, Bronx, New York.

PURPOSE. Patients with sickle cell disease have elevated circulating levels of cytokines including tumor necrosis factor (TNF) . TNF- stimulates expression by endothelial cells of adhesion molecules, including vascular cell adhesion molecule (VCAM) 1. Others have demonstrated that VLA-4 (₄ß₁), 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- increases retention of sickle erythrocytes in retina and if that retention can be inhibited.

METHODS. TNF- 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- 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 ₄ß₁ and ₄ß₇, or a monoclonal antibody against VLA-4 (19H8), significantly inhibited the TNF-–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 TNF- 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.

This article has been cited by other articles:

				M. J. Telen Role of Adhesion Molecules and Vascular Endothelium in the Pathogenesis of Sickle Cell Disease Hematology, January 1, 2007; 2007(1): 84 - 90. [Abstract] [Full Text] [PDF]

				D. G. Woodside, R. M. Kram, J. S. Mitchell, T. Belsom, M. J. Billard, B. W. McIntyre, and P. Vanderslice Contrasting Roles for Domain 4 of VCAM-1 in the Regulation of Cell Adhesion and Soluble VCAM-1 Binding to Integrin {alpha}4beta1. J. Immunol., April 15, 2006; 176(8): 5041 - 5049. [Abstract] [Full Text] [PDF]

				S. H. Embury, N. M. Matsui, S. Ramanujam, T. N. Mayadas, C. T. Noguchi, B. A. Diwan, N. Mohandas, and A. T. W. Cheung The contribution of endothelial cell P-selectin to the microvascular flow of mouse sickle erythrocytes in vivo Blood, November 15, 2004; 104(10): 3378 - 3385. [Abstract] [Full Text] [PDF]

				J. D. Holtzclaw, D. Jack, S. M. Aguayo, J. R. Eckman, J. Roman, and L. L. Hsu Enhanced Pulmonary and Systemic Response to Endotoxin in Transgenic Sickle Mice Am. J. Respir. Crit. Care Med., March 15, 2004; 169(6): 687 - 695. [Abstract] [Full Text] [PDF]

				X. Wei, J. M. Runnels, and C. P. Lin Selective Uptake of Indocyanine Green by Reticulocytes in Circulation Invest. Ophthalmol. Vis. Sci., October 1, 2003; 44(10): 4489 - 4496. [Abstract] [Full Text] [PDF]

				N. M. Matsui, A. Varki, and S. H. Embury Heparin inhibits the flow adhesion of sickle red blood cells to P-selectin Blood, November 15, 2002; 100(10): 3790 - 3796. [Abstract] [Full Text] [PDF]

				M K. Mathews, D S McLeod, C Merges, J Cao, and G A Lutty Neutrophils and leucocyte adhesion molecules in sickle cell retinopathy Br. J. Ophthalmol., June 1, 2002; 86(6): 684 - 690. [Abstract] [Full Text] [PDF]