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Intercellular Adhesion Molecule-1 Expression Is Required on Multiple Cell Types for the Development of Experimental Autoimmune Encephalomyelitis¹

Daniel C. Bullard^*, Xianzhen Hu, Trenton R. Schoeb^*, Robert G. Collins, Arthur L. Beaudet^¶ and Scott R. Barnum^2,,

^* Department of Genetics, Department of Microbiology, and Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294; and Department of Pediatrics and ^¶ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030

Many members of the Ig superfamily of adhesion molecules, such as ICAM-1 and VCAM-1, have been implicated in the pathogenesis of multiple sclerosis. Although it is well-established that VCAM-1/VLA-4 interactions can play important roles in mediating CNS inflammatory events in multiple sclerosis patients and during the development of experimental allergic encephalomyelitis (EAE), the contributions of ICAM-1 are poorly understood. This is due in large part to conflicting results from Ab inhibition studies and the observation of exacerbated EAE in ICAM-1 mutant mice that express a restricted set of ICAM-1 isoforms. To determine ICAM-1-mediated mechanisms in EAE, we analyzed ICAM-1 null mutant mice (ICAM-1^null), which express no ICAM-1 isoforms. ICAM-1^null mice had significantly attenuated EAE characterized by markedly reduced spinal cord T cell infiltration and IFN- production by these cells. Adoptive transfer of Ag-restimulated T cells from wild-type to ICAM-1^null mice or transfer of ICAM-1^null Ag-restimulated T cells to control mice failed to induce EAE. ICAM-1^null T cells also showed reduced proliferative capacity and substantially reduced levels of IFN-, TNF-, IL-4, IL-10, and IL-12 compared with that of control T cells following myelin oligodendrocyte glycoprotein 35–55 restimulation in vitro. Our results indicate that ICAM-1 expression is critical on T cells and other cell types for the development of demyelinating disease and suggest that expression of VCAM-1 and other adhesion molecules cannot fully compensate for the loss of ICAM-1 during EAE development.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Multiple Sclerosis Society Grant RG-3437-A-6 and National Institutes of Health Grants NS46032 (to S.R.B.) and RR017009 (to D.C.B.).

² Address correspondence and reprint requests to Dr. Scott R. Barnum, Department of Microbiology, University of Alabama at Birmingham, 845 19th Street South, Bevill Biomedical Research Building 842, Birmingham, AL 35294. E-mail address: sbarnum{at}uab.edu

³ Abbreviations used in this paper: MS, multiple sclerosis; MOG, myelin oligodendrocyte glycoprotein; EAE, experimental autoimmune encephalomyelitis; CDI, cumulative disease index; LFB, Luxol fast blue.

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