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The Journal of Neuroscience, March 25, 2009, 29(12):3816-3823; doi:10.1523/JNEUROSCI.5812-08.2009

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Neurobiology of Disease
Cytokine Switch and Bystander Suppression of Autoimmune Responses to Multiple Antigens in Experimental Autoimmune Encephalomyelitis by a Single Recombinant T-Cell Receptor Ligand

Sushmita Sinha,^1,2 Sandhya Subramanian,^1,2 Lisa Miller,^1,2 Thomas M. Proctor,^1,6 Chris Roberts,^1,2 Gregory G. Burrows,^2,3,6 Arthur A. Vandenbark,^1,2,4,6 and Halina Offner^1,2,5,6

¹Neuroimmunology Research, Veterans Affairs Medical Center, and ²Departments of Neurology, ³Biochemistry and Molecular Biology, ⁴Molecular Microbiology and Immunology, and ⁵Anesthesiology and Perioperative Medicine and ⁶Tykeson Multiple Sclerosis 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 SW US Veterans Hospital Road, Portland, OR 97239. Email: offnerva{at}ohsu.edu

Recombinant T-cell receptor ligands (RTLs) can 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). Antigen specificity of RTL raises the question as to whether this treatment would be successful in MS patients where target antigens are unknown. Using spinal cord homogenate or combinations of two different peptides to induce disease, we found that treatment with single RTL could reverse EAE as long as targeted T-cells were present. Therapy with three different RTLs each caused a significant reduction in IL-17 and increases in IL-10 and IL-13 in peptide-activated splenocytes, reduced proliferation of both cognate and bystander specificities of lymph node cells, and reduced inflammatory lesions and secreted IL-17 and IL-2 from peptide-activated spinal cord cells. These results show that treatment with single RTLs can induce a cytokine switch in cognate T-cells that inhibits both the target and bystander T-cells, providing new evidence for the potential applicability of RTL therapy in MS.

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Received Dec. 5, 2008; revised Jan. 30, 2009; accepted Feb. 17, 2009.

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

This article has been cited by other articles:

				L. Li, Z. Yi, B. Wang, and R. Tisch Suppression of Ongoing T Cell-Mediated Autoimmunity by Peptide-MHC Class II Dimer Vaccination J. Immunol., October 1, 2009; 183(7): 4809 - 4816. [Abstract] [Full Text] [PDF]

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