Neither T-helper type 2 nor Foxp3 + regulatory T cells are necessary for therapeutic benefit of atorvastatin in treatment of central nervous system autoimmunity
Martin S. Weber,Thomas Prod'homme,Sawsan Youssef,Shannon E. Dunn,Lawrence Steinman,Scott S. Zamvil +5 more
TLDR
Data imply that atorvastatin ameliorates central nervous system autoimmune disease primarily by inhibiting proliferation of proinflammatory encephalitogenic T cells, and not simply through induction of anti-inflammatory Th2 cells.Abstract:
Oral atorvastatin has prevented or reversed paralysis in the multiple sclerosis (MS) model experimental autoimmune encephalomyelitis (EAE), and reduced development of new MS lesions in clinical trials. Besides inhibiting development of encephalitogenic T cells, atorvastatin treatment of EAE has been associated with an induction of anti-inflammatory myelin-reactive T-helper type (Th)-2 cells. To investigate the clinical significance of atorvastatin-mediated Th2 differentiation, we first evaluated atorvastatin treatment in interleukin (IL)-4 green fluorescent protein-enhanced transcript (4-GET) reporter mice. Atorvastatin treatment failed to induce IL-4-producing Th2 cells in vivo; however, when T cells from atorvastatin-treated 4-GET mice were reactivated in vitro, T cells preferentially differentiated into Th2 cells, while antigen-specific T-cell proliferation and secretion of proinflammatory cytokines (interferon gamma, IL-17, tumor necrosis factor and IL-12) were reduced. Oral atorvastatin also prevented or reversed EAE in signal transducer and activator of transcription 6-deficient (STAT6−/−) mice, which cannot generate IL-4-producing Th2 cells. Further, atorvastatin treatment did not induce or expand Foxp3+ regulatory T cells in either wild-type or STAT6−/− mice. In vivo proliferation of T cells, as measured by incorporation of bromodeoxyuridine, was inhibited in atorvastatin-treated wild-type and STAT6−/− mice. These data imply that atorvastatin ameliorates central nervous system autoimmune disease primarily by inhibiting proliferation of proinflammatory encephalitogenic T cells, and not simply through induction of anti-inflammatory Th2 cells. This cytostatic effect may be a relevant mechanism of action when considering use of statins in MS and other inflammatory conditions.read more
Citations
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Journal ArticleDOI
Regulatory T cells in multiple sclerosis and myasthenia gravis
TL;DR: Several strategies of treatment which have been shown to be effective or are proposed as potential therapies to restore the function of various Treg subsets including Tr1, iTr35, nTregs, and iTregs appear promising for treating patients with MS or MG.
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Immune modulatory effects of statins.
TL;DR: The relevance of the different metabolites for the immunomodulatory effect of statins is discussed and preclinical results with data from clinical studies that tested statins for the treatment of different inflammatory diseases are connected.
Book ChapterDOI
STAT Transcription Factors in T Cell Control of Health and Disease.
Ritobrata Goswami,Mark H. Kaplan +1 more
TL;DR: The mechanism of how Jak-STAT signaling in T cells defines the authors' immune responses in the battle against foreign pathogens is discussed, leading to autoimmunity, allergic diseases, and cancer.
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Glycyrrhizin Protects Mice Against Experimental Autoimmune Encephalomyelitis by Inhibiting High-Mobility Group Box 1 (HMGB1) Expression and Neuronal HMGB1 Release.
Yan Sun,Huoying Chen,Jiapei Dai,Zhongjun Wan,Ping Xiong,Yong Xu,Zhengrong Han,Weitai Chai,Feili Gong,Fang Zheng +9 more
TL;DR: Results indicate that GL has a strong neuroprotective effect on EAE mice by reducing HMGB1 expression and release and thus can be used to treat central nervous system inflammatory diseases, such as MS.
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Protective and therapeutic role of 2-carba-cyclic phosphatidic acid in demyelinating disease.
Shinji Yamamoto,Kota Yamashina,Masaki Ishikawa,Mari Gotoh,Sosuke Yagishita,Kensuke Iwasa,Kei Maruyama,Kimiko Murakami-Murofushi,Keisuke Yoshikawa +8 more
TL;DR: It is demonstrated that 2ccPA protected oligodendrocytes via suppression of the mitochondrial apoptosis pathway and may be a promising compound for the development of new drugs to treat demyelinating disease and ameliorate the symptoms of multiple sclerosis.
References
More filters
Journal ArticleDOI
Glatiramer acetate reduces Th-17 inflammation and induces regulatory T-cells in the CNS of mice with relapsing-remitting or chronic EAE.
Rina Aharoni,Raya Eilam,Ariel Stock,Anya Vainshtein,Elias Shezen,Hilah Gal,Nir Friedman,Ruth Arnon +7 more
TL;DR: In mice treated with glatiramer acetate (GA, Copaxone), even when treatment started after disease exacerbation, CNS inflammation and Th-17 occurrence were drastically reduced, with parallel elevation in T-regulatory cells, indicating the immunomodulatory therapeutic consequences of GA treatment in situ.
Journal ArticleDOI
Regulation of gene expression associated with acute experimental autoimmune encephalomyelitis by Lovastatin.
Ajaib S. Paintlia,Manjeet K. Paintlia,Avtar K. Singh,Romesh Stanislaus,Anne G. Gilg,Ernest Barbosa,Inderjit Singh +6 more
TL;DR: Findings indicate that PPARs may be mediating the antiinflammatory and immunomodulatory effects of LOV, and provide new insight into the molecular events associated with the protection provided by statins during treatment of demyelinating diseases such as multiple sclerosis.
Journal ArticleDOI
Effect of glatiramer acetate (Copaxone) on CD4+CD25high T regulatory cells and their IL-10 production in multiple sclerosis
TL;DR: Examination of in vitro effects of GA on Tr cells from MS patients subgrouped according to treatment without or with disease-modulating drugs, and healthy controls concluded that GA induces elevated IL-10 production by Tr cells that is uniform and independent of ongoing MS treatment with IFN-beta or GA or IFn-beta+GA.
Journal ArticleDOI
Simvastatin treatment in patients with relapsing-remitting multiple sclerosis receiving interferon beta 1a: a double-blind randomized controlled trial.
Mansoureh Togha,Sanaz Ahmadi Karvigh,Masoud Nabavi,Nahid Beladi Moghadam,Mohammad Hossein Harirchian,Mohammad Ali Sahraian,Anahita Enzevaei,Alireza Nourian,Hossein Ghanaati,Kavous Firouznia,Ali Jannati,Majid Shekiba +11 more
TL;DR: This interventional study provides Class I evidence stating that adding simvastatin 40 mg/day to IFNb 1a 30 µg a week in patients with relapsing—remitting multiple sclerosis may reduce the relapse rate, and Mann—Whitney and one-way multivariate analysis of variances are used.
Journal ArticleDOI
Atorvastatin combined to interferon to verify the efficacy (ACTIVE) in relapsing-remitting active multiple sclerosis patients: a longitudinal controlled trial of combination therapy.
Roberta Lanzillo,Giuseppe Orefice,Mario Quarantelli,Carlo Rinaldi,Anna Prinster,G. Ventrella,Daniele Spitaleri,Giacomo Lus,G. Vacca,Barbara Carotenuto,Elena Salvatore,Arturo Brunetti,Gioacchino Tedeschi,Vincenzo Brescia Morra +13 more
TL;DR: Low-dose atorvastatin may be beneficial, as add-on therapy, in poor responders to high-dose interferon beta-1a alone, in multiple sclerosis patients responding poorly to interferons alone.