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

• Published in: The Journal of neuroscience Vol. 29; no. 12; pp. 3816 - 3823
• Main Authors: Sinha, Sushmita, Subramanian, Sandhya, Miller, Lisa, Proctor, Thomas M, Roberts, Chris, Burrows, Gregory G, Vandenbark, Arthur A, Offner, Halina
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 25.03.2009; Society for Neuroscience
• Subjects: Animals; Bystander Effect; Cytokines - metabolism; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - metabolism; Female; Ligands; Mice; Peptides - immunology; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell - metabolism; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - immunology; Recombinant Fusion Proteins - therapeutic use; Spinal Cord - immunology; Spinal Cord - pathology; T-Cell Antigen Receptor Specificity; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - pathology; Tissue Extracts - immunology
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/JNEUROSCI.5812-08.2009

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.