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.
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.
Jakubowski
A
A
Biogen, Inc., Cambridge, MA 02142, USA.
Ehrenfels
B N
BN
Pepinsky
R B
RB
Burkly
L C
LC
D000818:Animals; D015703:Antigens, CD / Q000187:drug effects*; D001327:Autoimmune Diseases / Q000517:prevention & control; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000517:prevention & control; D005260:Female; D007136:Immunoglobulins / Q000494:pharmacology; D016219:Immunotherapy, Adoptive; D039441:Integrin alpha4; D007515:Islets of Langerhans / Q000473:pathology; D008212:Lymphocyte Depletion; D008345:Manganese / Q000494:pharmacology; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D016688:Mice, Inbred NOD; D016029:Receptors, Very Late Antigen / Q000187:drug effects*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000494:pharmacology*
D015703:Antigens, CD; D007136:Immunoglobulins; D016029:Receptors, Very Late Antigen; D011993:Recombinant Fusion Proteins; D019010:Vascular Cell Adhesion Molecule-1; D039441:Integrin alpha4; D008345:Manganese; D008727:Methotrexate