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

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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.

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Acknowledgments

This research was supported in part by the Intramural Research Program of the National Institute on Aging.

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The authors have no financial conflicts of interest.

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Authors and Affiliations

  1. Laboratory of Cell Biology and Immunology, National Institute on Aging, Intramural Research Program, Baltimore, MD, 21224, USA

    Jun-Ho Lee, Dolgar Baatar, Hyun-Jin Tae, Jie-Wan Kim, Arnell Carter, Ana Lustig & Dennis D. Taub

  2. Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, Baltimore, MD, 21224, USA

    Jun-Ho Lee, Mohamed R. Mughal & Mark P. Mattson

  3. The Mina and Everard Goodman Faculty of Life Sciences, Bar‐Ilan University, 52900, Ramat Gan, Israel

    Meital Halperin-Sheinfeld, Omri Snir, Eitan Okun & Benjamin Sredni

  4. Blood Transfusion Center, Sheba Medical Center, Tel-Hashomer, Israel

    Omri Snir & Gad Lavie

  5. Multiple Sclerosis Center, Sheba Medical Center, Tel-Hashomer, Israel

    Omri Snir & Gad Lavie

  6. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Mark P. Mattson

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  1. Jun-Ho Lee
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Correspondence to Mark P. Mattson, Benjamin Sredni or Dennis D. Taub.

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Jun-Ho Lee and Meital Halperin-Sheinfeld have contributed equally to acquisition and analysis of data in this study.

Mark P. Mattson, Benjamin Sredni and Dennis D. Taub made equal contributions as senior authors.

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Lee, JH., Halperin-Sheinfeld, M., Baatar, D. et al. Tellurium Compound AS101 Ameliorates Experimental Autoimmune Encephalomyelitis by VLA-4 Inhibition and Suppression of Monocyte and T Cell Infiltration into the CNS. Neuromol Med 16, 292–307 (2014). https://doi.org/10.1007/s12017-013-8277-3

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