NeuroMolecular Medicine

, Volume 16, Issue 2, pp 292–307

Tellurium Compound AS101 Ameliorates Experimental Autoimmune Encephalomyelitis by VLA-4 Inhibition and Suppression of Monocyte and T Cell Infiltration into the CNS

  • Jun-Ho Lee
  • Meital Halperin-Sheinfeld
  • Dolgar Baatar
  • Mohamed R. Mughal
  • Hyun-Jin Tae
  • Jie-Wan Kim
  • Arnell Carter
  • Ana Lustig
  • Omri Snir
  • Gad Lavie
  • Eitan Okun
  • Mark P. Mattson
  • Benjamin Sredni
  • Dennis D. Taub
Original Paper

DOI: 10.1007/s12017-013-8277-3

Cite this article as:
Lee, JH., Halperin-Sheinfeld, M., Baatar, D. et al. Neuromol Med (2014) 16: 292. doi:10.1007/s12017-013-8277-3

Abstract

Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system (CNS) involving demyelinating and neurodegenerative processes. Several of the major pathological CNS alterations and behavioral deficits of MS are recapitulated in the experimental autoimmune encephalitis (EAE) mouse model in which the disease process is induced by administration of myelin peptides. Development of EAE requires infiltration of inflammatory cytokine-generating monocytes and macrophages, and auto-reactive T cells, into the CNS. Very late antigen-4 (VLA-4, α4β1) is an integrin molecule that plays a role in inflammatory responses by facilitating the migration of leukocytes across the blood–brain barrier during inflammatory disease, and antibodies against VLA-4 exhibit therapeutic efficacy in mouse and monkey MS models. Here, we report that the tellurium compound AS101 (ammonium trichloro (dioxoethylene-o,o′) tellurate) ameliorates EAE by inhibiting monocyte and T cell infiltration into the CNS. CD49d is an alpha subunit of the VLA-4 (α4β1) integrin. During the peak stage of EAE, AS101 treatment effectively ameliorated the disease process by reducing the number of CD49d+ inflammatory monocyte/macrophage cells in the spinal cord. AS101 treatment markedly reduced the pro-inflammatory cytokine levels, while increasing anti-inflammatory cytokine levels. In contrast, AS101 treatment did not affect the peripheral populations of CD11b+ monocytes and macrophages. AS101 treatment reduced the infiltration of CD4+ and CD49+/VLA4 T cells. In addition, treatment of T cells from MS patients with AS101 resulted in apoptosis, while such treatment did not affect T cells from healthy donors. These results suggest that AS101 reduces accumulation of leukocytes in the CNS by inhibiting the activity of the VLA-4 integrin and provide a rationale for the potential use of Tellurium IV compounds for the treatment of MS.

Keywords

Inflammation Integrin Macrophages Multiple sclerosis Spinal cord VLA-4 

Supplementary material

12017_2013_8277_MOESM1_ESM.docx (14 kb)
Supplementary material 1 (DOCX 14 kb)

Copyright information

© Springer Science+Business Media New York (outside the USA) 2013

Authors and Affiliations

  • Jun-Ho Lee
    • 1
    • 2
  • Meital Halperin-Sheinfeld
    • 3
  • Dolgar Baatar
    • 1
  • Mohamed R. Mughal
    • 2
  • Hyun-Jin Tae
    • 1
  • Jie-Wan Kim
    • 1
  • Arnell Carter
    • 1
  • Ana Lustig
    • 1
  • Omri Snir
    • 3
    • 4
    • 5
  • Gad Lavie
    • 4
    • 5
  • Eitan Okun
    • 3
  • Mark P. Mattson
    • 2
    • 6
  • Benjamin Sredni
    • 3
  • Dennis D. Taub
    • 1
  1. 1.Laboratory of Cell Biology and ImmunologyNational Institute on Aging, Intramural Research ProgramBaltimoreUSA
  2. 2.Laboratory of NeurosciencesNational Institute on Aging, Intramural Research ProgramBaltimoreUSA
  3. 3.The Mina and Everard Goodman Faculty of Life SciencesBar‐Ilan UniversityRamat GanIsrael
  4. 4.Blood Transfusion CenterSheba Medical CenterTel-HashomerIsrael
  5. 5.Multiple Sclerosis CenterSheba Medical CenterTel-HashomerIsrael
  6. 6.Department of NeuroscienceJohns Hopkins University School of MedicineBaltimoreUSA

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