The Journal of Immunology, Vol 155, Issue 2 938-946, Copyright © 1995 by American Association of Immunologists

ARTICLES

Vascular cell adhesion molecule-Ig fusion protein selectively targets activated alpha 4-integrin receptors in vivo. Inhibition of autoimmune diabetes in an adoptive transfer model in nonobese diabetic mice

A Jakubowski, BN Ehrenfels, RB Pepinsky and LC Burkly
Biogen, Inc., Cambridge, MA 02142, USA.

The alpha 4 beta 1-integrin (CD49d, CD29) constitutively expressed on leukocytes regulates cell migration to inflammatory sites, cell activation, and development through its interactions with two alternate ligands, vascular cell adhesion molecule-1 (VCAM-1; CD106) expressed on cytokine-activated endothelium, dendritic and stromal cells, and the extracellular matrix protein fibronectin. Another alpha 4-integrin receptor, alpha 4 beta 7, expressed on leukocytes also binds VCAM-1 and fibronectin (FN), and controls homing to mucosal tissues through its interactions with mucosal vascular addressin MAdCAM-1. In vitro studies have shown that alpha 4-dependent cell adhesion is regulated by the activation state of the cell and by divalent cations. However, the existence and role of cells with different alpha 4 activation states in vivo have not been defined. Herein we show that a soluble ligand with the two N-terminal domains of human VCAM-1 fused to a human IgG1 constant region, VCAM-Ig, binds selectively to activated alpha 4- receptors on murine cells, such as those induced by Mn2+ in vitro. To determine whether the cells identified by VCAM-Ig were required under physiologic conditions, we assessed its anti-inflammatory effect. We show that VCAM-Ig is not bound to the majority of murine alpha 4+ cells after in vivo administration, yet it significantly delays the onset of adoptively transferred autoimmune diabetes. Thus, soluble VCAM-Ig can modify alpha 4-dependent disease progression, apparently by its selective action on cells with activated alpha 4-integrin receptors, thereby providing evidence for distinct alpha 4 activation states in vivo.

This article has been cited by other articles:

				S. S. Vukkadapu, J. M. Belli, K. Ishii, A. G. Jegga, J. J. Hutton, B. J. Aronow, and J. D. Katz Dynamic interaction between T cell-mediated {beta}-cell damage and {beta}-cell repair in the run up to autoimmune diabetes of the NOD mouse Physiol Genomics, April 14, 2005; 21(2): 201 - 211. [Abstract] [Full Text] [PDF]

				G. C. Koo, K. Shah, G. J. F. Ding, J. Xiao, R. Wnek, G. Doherty, X. C. Tong, R. B. Pepinsky, K.-C. Lin, W. K. Hagmann, et al. A Small Molecule Very Late Antigen-4 Antagonist Can Inhibit Ovalbumin-induced Lung Inflammation Am. J. Respir. Crit. Care Med., May 15, 2003; 167(10): 1400 - 1409. [Abstract] [Full Text] [PDF]

				J. R. Chan, S. J. Hyduk, and M. I. Cybulsky Chemoattractants Induce a Rapid and Transient Upregulation of Monocyte {alpha}4 Integrin Affinity for Vascular Cell Adhesion Molecule 1 Which Mediates Arrest: An Early Step in the Process of Emigration J. Exp. Med., May 14, 2001; 193(10): 1149 - 1158. [Abstract] [Full Text] [PDF]

				C. Bartholdy, O. Marker, and A. R. Thomsen Migration of activated CD8+ T lymphocytes to sites of viral infection does not require endothelial selectins Blood, February 15, 2000; 95(4): 1362 - 1369. [Abstract] [Full Text] [PDF]

				D. T. Loo, S. B. Kanner, and A. Aruffo Filamin Binds to the Cytoplasmic Domain of the beta 1-Integrin. IDENTIFICATION OF AMINO ACIDS RESPONSIBLE FOR THIS INTERACTION J. Biol. Chem., September 4, 1998; 273(36): 23304 - 23312. [Abstract] [Full Text] [PDF]

				T. A. Yednock, C. Cannon, C. Vandevert, E. G. Goldbach, G. Shaw, D. K. Ellis, C. Liaw, L. C. Fritz, and L. I. Tanner alpha(4)beta(1)Integrin-dependent Cell Adhesion Is Regulated by a Low Affinity Receptor Pool That Is Conformationally Responsive to Ligand J. Biol. Chem., December 1, 1995; 270(48): 28740 - 28750. [Abstract] [Full Text] [PDF]