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
Reads0
Chats0
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
More filters
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.
Journal ArticleDOI
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.
Journal ArticleDOI
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.
Journal ArticleDOI
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
Immunomodulation of experimental autoimmune encephalomyelitis in the Lewis rats by Lovastatin
TL;DR: This study documents for the first time that Lovastatin induces a bias towards Th2 cytokines ex vivo, and as a result may be of therapeutic value for cell-mediated diseases such as multiple sclerosis.
Journal ArticleDOI
Suppression of Autoimmune Retinal Disease by Lovastatin Does Not Require Th2 Cytokine Induction
Matthew E. Gegg,R Harry,Deborah J.R. Hankey,H. Zambarakji,Gareth Pryce,David Baker,Peter Adamson,Calder,John Greenwood +8 more
TL;DR: It is shown that treatment with the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, lovastatin, suppresses clinical ocular pathology, retinal vascular leakage, and leukocytic infiltration into the retina in an acute mouse model of autoimmune retinal disease, and the potential differential activity of statins in different inflammatory conditions is highlighted.
Journal ArticleDOI
Effects of atorvastatin on the Th1/Th2 polarization of ongoing experimental autoimmune myocarditis in Lewis rats.
TL;DR: The results demonstrate an important role of Th1/Th2 polarization in the pathogenesis of EAM and suggest that HMG-CoA reductase blockade may be a promising new strategy for the treatment of organ specific autoimmune diseases.
Journal ArticleDOI
Statins in the treatment of central nervous system autoimmune disease.
Martin S. Weber,Sawsan Youssef,Shannon E. Dunn,Thomas Prod'homme,Oliver Neuhaus,Olaf Stüve,John Greenwood,Lawrence Steinman,Scott S. Zamvil +8 more
TL;DR: In experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis (MS), statins prevent or reverse paralysis and were recently shown to exert synergistic benefit when combined with agents approved for MS therapy.
Journal ArticleDOI
HMG-CoA reductase inhibitor attenuates experimental autoimmune myocarditis through inhibition of T cell activation.
Ryoko Wakizono Azuma,Jun-ichi Suzuki,Masahito Ogawa,Hideki Futamatsu,Noritaka Koga,Yasuyuki Onai,Hisanori Kosuge,Mitsuaki Isobe +7 more
TL;DR: Fluvastatin ameliorates EAM by inhibiting T cell responses and suppressing Th1-type and inflammatory cytokines via inactivation of nuclear factor-kappaB, and this activity is independent of cholesterol reduction.