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, Sandhya Subramanian, Thomas M. Proctor, Laurie J. Kaler, Marjorie Grafe, Rony Dahan, Jianya Huan, Arthur Vandenbark, Gregory G. Burrows, Halina Offner

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

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-Ab 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 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.

Original languageEnglish (US)
Pages (from-to)12531-12539
Number of pages9
JournalJournal of Neuroscience
Volume27
Issue number46
DOIs
StatePublished - Nov 14 2007

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Autoimmune Experimental Encephalomyelitis
Interleukin-17
T-Cell Antigen Receptor
Multiple Sclerosis
Cell Movement
Ligands
T-Lymphocytes
Spinal Cord
Myelin-Oligodendrocyte Glycoprotein
Myelitis
Therapeutics
Antigens
Vascular Cell Adhesion Molecule-1
Chemokine Receptors
Intercellular Adhesion Molecule-1
Green Fluorescent Proteins
Inbred C57BL Mouse
Immunotherapy
Down-Regulation
Endothelial Cells

Keywords

  • Chemokines/receptors
  • CNS
  • EAE
  • IL-17
  • RTL
  • SH

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

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. / Sinha, Sushmita; Subramanian, Sandhya; Proctor, Thomas M.; Kaler, Laurie J.; Grafe, Marjorie; Dahan, Rony; Huan, Jianya; Vandenbark, Arthur; Burrows, Gregory G.; Offner, Halina.

In: Journal of Neuroscience, Vol. 27, No. 46, 14.11.2007, p. 12531-12539.

Research output: Contribution to journalArticle

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abstract = "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-Ab 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 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.",
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