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- Title
Immunomodulatory synergy by combination of atorvastatin and glatiramer acetate in treatment of CNS autoimmunity.
- Authors
Stüve, Olaf; Youssef, Sawsan; Weber, Martin S.; Nessler, Stefan; von Budingen, Hans-Christian; Hemmer, Bernhard; Prod'homme, Thomas; Sobel, Raymond A.; Steinman, Lawrence; Zamvil, Scott S.; Stüve, Olaf; von Büdingen, Hans-Christian
- 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.
- Subjects
IMMUNOLOGICAL adjuvants; CENTRAL nervous system; AUTOIMMUNITY; HYDROXYMETHYLGLUTARYL coenzyme A reductases; TH2 cells; CYTOKINES; ANIMAL experimentation; CELL culture; COMBINATION drug therapy; COMPARATIVE studies; DEMYELINATION; FATTY acids; HETEROCYCLIC compounds; MICE; MONOCYTES; MULTIPLE sclerosis; PEPTIDES; RESEARCH funding; T cells; PHARMACODYNAMICS; THERAPEUTICS
- Publication
Journal of Clinical Investigation, 2006, Vol 116, Issue 4, p1037
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI25805