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
| Autor: | Marjorie R. Grafe, Gregory G. Burrows, Sandhya Subramanian, Halina Offner, Laurie J. Kaler, Arthur A. Vandenbark, Rony Dahan, Sushmita Sinha, Thomas M. Proctor, Jianya Huan |
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| Rok vydání: | 2007 |
| Předmět: |
Male
Chemokine Encephalomyelitis Autoimmune Experimental Multiple Sclerosis Recombinant Fusion Proteins T-Lymphocytes Green Fluorescent Proteins Receptors Antigen T-Cell Down-Regulation Inflammation Ligands Mice Myelin Cell Movement medicine Animals Immunologic Factors Cell adhesion biology Tumor Necrosis Factor-alpha General Neuroscience Multiple sclerosis Interleukin-17 Experimental autoimmune encephalomyelitis Articles medicine.disease Peptide Fragments Oligodendrocyte Mice Inbred C57BL Treatment Outcome medicine.anatomical_structure Immunology biology.protein Immunotherapy Interleukin 17 Chemokines medicine.symptom Cell Adhesion Molecules |
| Zdroj: | The Journal of Neuroscience. 27:12531-12539 |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.3599-07.2007 |
| Popis: | 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 α1 and β1 domains of the I-Abclass 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 α 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. |
| Databáze: | OpenAIRE |
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