Treatment of delayed-type hypersensitivity with inhibitors of the VLA-4 integrin

Abstract

Delayed-type hypersensitivity (DTH) is a skin inflammatory response induced by sensitization with an antigenic substance. We have previously reported a murine adoptive model of DTH to the chemical oxazalone elicited by transferring primed T lymphocytes into naive recipient mice [8]. Moreover, we and others have shown that the VLA-4 integrin (c~4/31, CD49d/CD29) is a major mediator of cutaneous DTH [6, 8, 10, 11, 17, 18, 31]. VLA-4 is an integrin cell adhesion receptor primarily expressed on lymphocytes, monocytes, and eosinophils, but not on neutrophils [14, 15]. VLA-4-mediated adhesion occurs through direct molecular interaction with either of two separate counterreceptors (ligands) on the opposingcell. These are vascular cell adhesion molecule-1 (VCAM-1) [5, 7, 30], and alternatively spliced variants of fibronectin containing CS-1 [13, 33]. VCAM-1 is a member of the immunoglobulin gene superfamily expressed on a variety of cell types [12], while CS-1 is a 25-amino acid sequence which arises by alternative splicing of fibronectin [16]. Recently, we observed that CS-1 fibronectin was selectively expressed in synovial tissue obtained from biopsies of rheumatoid arthritis (RA) patients, but not in normal synovium [9]. This was thoroughly unexpected because fibronectin is known as a ubiquitous extracellular matrix protein, yet the CS-1 variant of fibronectin was only found on RA blood vessels [9]. This finding raised the prospect that CS-1 splicing and, especially, CS-1 fibronectin could play a role in extravasation of leukocytes from the bloodstream. In this regard, it has been shown that the VLA-4/CS-1 fibronectin interaction is involved in the transmigration of eosinophils across an endothelial cell barrier in an in vitro assay system [19].

DOI: 10.1007/BF00196099

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@article{Tamraz1995TreatmentOD, title={Treatment of delayed-type hypersensitivity with inhibitors of the VLA-4 integrin}, author={Susan Tamraz and Thomas Arrhenius and Anthony Chiem and Michael J. Forrest and Federico C. A. Gaeta and Ya-Bo He and Jia Lei and Ajesh Maewal and M. Laurie Phillips and Leanne W. Vollger and Mariano J. Elkes}, journal={Springer Seminars in Immunopathology}, year={1995}, volume={16}, pages={437-441} }