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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.
J Immunol. 1995 Jul 15; 155(2):938-46.JI

Abstract

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.

Authors+Show Affiliations

Biogen, Inc., Cambridge, MA 02142, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

7608569

Citation

Jakubowski, A, et al. "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." Journal of Immunology (Baltimore, Md. : 1950), vol. 155, no. 2, 1995, pp. 938-46.
Jakubowski A, Ehrenfels BN, Pepinsky RB, et al. 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. J Immunol. 1995;155(2):938-46.
Jakubowski, A., Ehrenfels, B. N., Pepinsky, R. B., & Burkly, L. C. (1995). 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. Journal of Immunology (Baltimore, Md. : 1950), 155(2), 938-46.
Jakubowski A, et al. 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. J Immunol. 1995 Jul 15;155(2):938-46. PubMed PMID: 7608569.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Jakubowski,A, AU - Ehrenfels,B N, AU - Pepinsky,R B, AU - Burkly,L C, PY - 1995/7/15/pubmed PY - 1995/7/15/medline PY - 1995/7/15/entrez SP - 938 EP - 46 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J Immunol VL - 155 IS - 2 N2 - 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. SN - 0022-1767 UR - https://www.unboundmedicine.com/medline/citation/7608569/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_ L2 - https://www.jimmunol.org/lookup/pmidlookup?view=long&pmid=7608569 DB - PRIME DP - Unbound Medicine ER -