Immunomodulatory synergy by combination of atorvastatin and glatiramer acetate in treatment of CNS autoimmunity

Olaf Stüve, Sawsan Youssef, Martin S. Weber, Stefan Nessler, Hans Christian Von Büdingen, Bernhard Hemmer, Thomas Prod'homme, Raymond A. Sobel, Lawrence Steinman, Scott S. Zamvil

Research output: Contribution to journalArticle

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Abstract

One approach to improving efficacy in MS therapy is to identify medications that provide additive or synergistic benefit in combination. Orally administered cholesterol-lowering HMG-CoA reductase inhibitors (known as statins), which exhibit immunomodulatory properties and are effective in treatment of the MS model EAE, are being tested in MS. As atorvastatin can enhance protective Th2 responses and has a different mechanism of action than glatiramer acetate (GA), a parenterally administered immunomodulatory agent approved for MS treatment, we tested whether the combination of these agents could be beneficial in EAE. Combination therapy using suboptimal doses of atorvastatin and GA prevented or reversed clinical and histologic EAE. Secretion of proinflammatory Th1 cytokines was reduced - and conversely Th2 cytokine secretion was increased - in these mice, but not in mice treated with each drug alone at the same doses. Monocytes treated with the combination of suboptimal doses of atorvastatin and GA secreted an antiinflammatory type II cytokine pattern and, when used as APCs, promoted Th2 differentiation of naive myelin-specific T cells. Our results demonstrate that agents with different mechanisms of immune modulation can combine in a synergistic manner for the treatment of CNS autoimmunity and provide rationale for testing the combination of atorvastatin and GA in MS.

Original languageEnglish (US)
Pages (from-to)1037-1044
Number of pages8
JournalJournal of Clinical Investigation
Volume116
Issue number4
DOIs
StatePublished - Apr 1 2006

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Autoimmunity
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Cytokines
Myelin Sheath
Monocytes
Anti-Inflammatory Agents
Cholesterol
T-Lymphocytes
Glatiramer Acetate
Atorvastatin Calcium
Therapeutics
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Stüve, O., Youssef, S., Weber, M. S., Nessler, S., Von Büdingen, H. C., Hemmer, B., ... Zamvil, S. S. (2006). Immunomodulatory synergy by combination of atorvastatin and glatiramer acetate in treatment of CNS autoimmunity. Journal of Clinical Investigation, 116(4), 1037-1044. https://doi.org/10.1172/JCI25805

Immunomodulatory synergy by combination of atorvastatin and glatiramer acetate in treatment of CNS autoimmunity. / Stüve, Olaf; Youssef, Sawsan; Weber, Martin S.; Nessler, Stefan; Von Büdingen, Hans Christian; Hemmer, Bernhard; Prod'homme, Thomas; Sobel, Raymond A.; Steinman, Lawrence; Zamvil, Scott S.

In: Journal of Clinical Investigation, Vol. 116, No. 4, 01.04.2006, p. 1037-1044.

Research output: Contribution to journalArticle

Stüve, O, Youssef, S, Weber, MS, Nessler, S, Von Büdingen, HC, Hemmer, B, Prod'homme, T, Sobel, RA, Steinman, L & Zamvil, SS 2006, 'Immunomodulatory synergy by combination of atorvastatin and glatiramer acetate in treatment of CNS autoimmunity', Journal of Clinical Investigation, vol. 116, no. 4, pp. 1037-1044. https://doi.org/10.1172/JCI25805
Stüve, Olaf ; Youssef, Sawsan ; Weber, Martin S. ; Nessler, Stefan ; Von Büdingen, Hans Christian ; Hemmer, Bernhard ; Prod'homme, Thomas ; Sobel, Raymond A. ; Steinman, Lawrence ; Zamvil, Scott S. / Immunomodulatory synergy by combination of atorvastatin and glatiramer acetate in treatment of CNS autoimmunity. In: Journal of Clinical Investigation. 2006 ; Vol. 116, No. 4. pp. 1037-1044.
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