Immunomodulatory synergy by combination of atorvastatin and glatiramer acetate in treatment of CNS autoimmunity.
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.
Department of Neurology and Program in Immunology, University of California, San Francisco, San Francisco, California, USA.
Olaf
O
Stüve
Sawsan
S
Youssef
Martin S
MS
Weber
Stefan
S
Nessler
Hans-Christian
HC
von Büdingen
Bernhard
B
Hemmer
Thomas
T
Prod'homme
Raymond A
RA
Sobel
Lawrence
L
Steinman
Scott S
SS
Zamvil
D000818:Animals; D000069059:Atorvastatin; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004359:Drug Therapy, Combination; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy*; D005260:Female; D000068717:Glatiramer Acetate; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D007155:Immunologic Factors / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008815:Mice, Inbred Strains; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology
D016207:Cytokines; D006538:Heptanoic Acids; D007155:Immunologic Factors; D010455:Peptides; D011758:Pyrroles; D000068717:Glatiramer Acetate; D000069059:Atorvastatin