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The Journal of Neuroscience, November 14, 2007, 27(46):12531-12539; doi:10.1523/JNEUROSCI.3599-07.2007

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Neurobiology of Disease
A Promising Therapeutic Approach for Multiple Sclerosis: Recombinant T-Cell Receptor Ligands Modulate Experimental Autoimmune Encephalomyelitis by Reducing Interleukin-17 Production and Inhibiting Migration of Encephalitogenic Cells into the CNS

Sushmita Sinha,^1,2 Sandhya Subramanian,¹ Thomas M. Proctor,^1,7 Laurie J. Kaler,¹ Marjorie Grafe,^3,4 Rony Dahan,^2,3 Jianya Huan,^2,7 Arthur A. Vandenbark,^1,2,5,7 Gregory G. Burrows,^2,6,7 and Halina Offner^1,2,4,7

¹Neuroimmunology Research, Veterans Affairs Medical Center, Portland, Oregon 97239, and Departments of ²Neurology, ³Pathology, ⁴Anesthesiology and Perioperative Medicine, ⁵Molecular Microbiology and Immunology, and ⁶Biochemistry and Molecular Biology and ⁷Tykeson MS Research Laboratory, Oregon Health & Science University, Portland, Oregon 97239

Correspondence should be addressed to Dr. Halina Offner, Neuroimmunology Research R&D-31, Portland Veterans Affairs Medical Center, 3710 Southwest U.S. Veterans Hospital Road, Portland, OR 97239. Email: offnerva{at}ohsu.edu

Recombinant T-cell receptor ligands (RTLs) can prevent and reverse clinical and histological signs of experimental autoimmune encephalomyelitis (EAE) in an antigen-specific manner and are currently in clinical trials for treatment of subjects with multiple sclerosis (MS). To evaluate regulatory mechanisms, we designed and tested RTL551, containing the 1 and ß1 domains of the I-A^b class II molecule covalently linked to the encephalitogenic MOG-35-55 peptide in C57BL/6 mice. Treatment of active or passive EAE with RTL551 after disease onset significantly reduced clinical signs and spinal cord lesions. Moreover, RTL551 treatment strongly and selectively reduced secretion of interleukin-17 and tumor necrosis factor by transferred green fluorescent protein-positive (GFP+) MOG-35-55-reactive T-cells and almost completely abrogated existent GFP+ cellular infiltrates in affected spinal cord sections. Reduced inflammation in spinal cords of RTL551-treated mice was accompanied by a highly significant downregulation of chemokines and their receptors and inhibition of VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) expression by endothelial cells. Thus, RTL therapy cannot only inhibit systemic production of encephalitogenic cytokines by the targeted myelin oligodendrocyte glycoprotein-reactive T-cells but also impedes downstream local recruitment and retention of inflammatory cells in the CNS. These findings indicate that targeted immunotherapy of antigen-specific T-cells can result in a reversal of CNS lesion formation and lend strong support to the application of the RTL approach for therapy in MS.

Key words: EAE; RTL; CNS; IL-17; chemokines/receptors; SH

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Received Aug. 8, 2007; revised Sept. 19, 2007; accepted Oct. 2, 2007.

Correspondence should be addressed to Dr. Halina Offner, Neuroimmunology Research R&D-31, Portland Veterans Affairs Medical Center, 3710 Southwest U.S. Veterans Hospital Road, Portland, OR 97239. Email: offnerva{at}ohsu.edu

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