Simvastatin ameliorates experimental autoimmune encephalomyelitis by inhibiting Th1/Th17 response and cellular infiltration

Oliveira, Daniel May de; Oliveira, Enedina Maria Lobato de; Ferrari, Merari F. R.; Semedo, Patrícia; Hiyane, Meire Ioshie; Cenedeze, Marcos Antônio; Pacheco-Silva, Álvaro; Câmara, Niels Olsen Saraiva; Peron, Jean Pierre Schatzmann

doi:10.1007/s10787-015-0252-1

Cited by 27 publications

(20 citation statements)

References 61 publications

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“…37 In agreement with these findings the authors also reported lower central nervous system inflammatory mononuclear cell levels and less Th1 and Th17 cell infiltration in the central nervous system. 37 Furthermore, simvastatin diminished the proliferation of T cells co-cultured with primary microglial cells. Although the initial studies had suggested that statin treatment causes a Th2 induction, follow-up reports showed that atorvastatin treatment did not induce IL-4-producing Th2 cells in vivo.…”

Section: Statins In Mssupporting

confidence: 74%

“…36 A more recent study in which mice were immunized with myelin oligodendrocyte glycoprotein, showed that the treatment with simvastatin improved clinical disease scores. 37 Additionally, anti-inflammatory transforming growth factor-b mRNA expression was increased while IL-6, IL-12p40, IL-12p70, RANTES and macrophage inflammatory protein-1b were decreased. 37 In agreement with these findings the authors also reported lower central nervous system inflammatory mononuclear cell levels and less Th1 and Th17 cell infiltration in the central nervous system.…”

Section: Statins In Msmentioning

confidence: 98%

“…37 Additionally, anti-inflammatory transforming growth factor-b mRNA expression was increased while IL-6, IL-12p40, IL-12p70, RANTES and macrophage inflammatory protein-1b were decreased. 37 In agreement with these findings the authors also reported lower central nervous system inflammatory mononuclear cell levels and less Th1 and Th17 cell infiltration in the central nervous system. 37 Furthermore, simvastatin diminished the proliferation of T cells co-cultured with primary microglial cells.…”

Section: Statins In Msmentioning

confidence: 98%

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Immune modulatory effects of statins

2018

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SummaryDespite major advances in recent years, immunosuppressive regimens for multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus and graft-versus-host disease still have major adverse effects and immunomodulation rather than immune paralysis would be desirable. Statins inhibit the rate-limiting enzyme of the L-mevalonate pathway, the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase. It was shown that blocking the L-mevalonate pathway reduces inflammation through effects on downstream metabolites of the pathway including farnesylpyrophosphates and geranylgeranylpyrophosphates, which are essential for the attachment of GTPases like RhoA, Rac and Ras to the cell membrane. Therefore, Lmevalonate pathway downstream products play critical roles in the different steps of an immune response including immune cell activation, migration, cytokine production, immune metabolism and survival. This review discusses the relevance of the different metabolites for the immunomodulatory effect of statins and connects preclinical results with data from clinical studies that tested statins for the treatment of different inflammatory diseases.

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Section: Statins In Mssupporting

confidence: 74%

Section: Statins In Msmentioning

confidence: 98%

Section: Statins In Msmentioning

confidence: 98%

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Immune modulatory effects of statins

2018

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“…Simvastatin exhibits its immunomodulatory action by impacting the Th1 and Th17 as well as by modulation the dendritic cells (86, 87). …”

Section: Current and Possible Future Treatmentsmentioning

confidence: 99%

Primary Progressive Multiple Sclerosis: Putting Together the Puzzle

2017

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The focus of multiple sclerosis research has recently turned to the relatively rare and clearly more challenging condition of primary progressive multiple sclerosis (PPMS). Many risk factors such as genetic susceptibility, age, and Epstein–Barr virus (EBV) infection may interdepend on various levels, causing a complex pathophysiological cascade. Variable pathological mechanisms drive disease progression, including inflammation-associated axonal loss, continuous activation of central nervous system resident cells, such as astrocytes and microglia as well as mitochondrial dysfunction and iron accumulation. Histological studies revealed diffuse infiltration of the gray and white matter as well as of the meninges with inflammatory cells such as B-, T-, natural killer, and plasma cells. While numerous anti-inflammatory agents effective in relapsing remitting multiple sclerosis basically failed in treatment of PPMS, the B-cell-depleting monoclonal antibody ocrelizumab recently broke the dogma that PPMS cannot be treated by an anti-inflammatory approach by demonstrating efficacy in a phase 3 PPMS trial. Other treatments aiming at enhancing remyelination (MD1003) as well as EBV-directed treatment strategies may be promising agents on the horizon. In this article, we aim to summarize new advances in the understanding of risk factors, pathophysiology, and treatment of PPMS. Moreover, we introduce a novel concept to understand the nature of the disease and possible treatment strategies in the near future.

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“…Some studies demonstrated that Treg cells can not properly infiltrate in CNS during the disease course (de Oliveira et al, 2015;Müller et al, 2007;Fritzsching et al, 2011). Inefficient migration of Treg cells to neuroinflammatory sites lead to profound implications (Keil et al, 2016;Buckner, 2010).…”

Section: Discussionmentioning

confidence: 99%

Increased frequency of CD4+CD25high CD127low regulatory T cells in patients with multiple sclerosis

et al. 2019

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A B S T R A C TBackground: Multiple sclerosis (MS), one of the most common diseases of the central nervous system (CNS), is characterized by demyelination and chronic inflammation of the CNS. Failure of immune tolerance and induced autoimmune processes are involved in MS immunopathogenesis. Regulatory T (Treg) cells play an important role in maintaining peripheral tolerance and immune homeostasis. Objective: The aim of this study was to evaluate the frequency of CD4 + CD25 high CD127 low/− Treg cells in MS patients. Methods: The study population was composed of 25 healthy controls (HCs), 35 patients with relapsing remitting multiple sclerosis (RRMS) and 25 patients with progressive multiple sclerosis (PMS). Frequency of CD4 + CD25 high CD127 low/− Treg cells in RRMS and PMS patients was compared with HC by flow cytometry. Results: Treg cells frequency in PMS patients was significantly higher compared to RRMS patients (P < 0.001) and HCs (P < 0.001). It was lower in RRMS patients than HCs (P = 0.005). A Significant direct correlation between Treg cells frequency and expanded disability status scale (EDSS) in PMS patients (P = 0.001, r = 0.6) was observed. Reverse correlation between Treg cells frequency and EDSS in RRMS patients was found (P = 0.01, r = −0.4). Conclusion: More detailed clarification of the role of Treg cells in MS patients could provide a basis for development of Treg cells-mediated therapeutic strategies.

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Simvastatin ameliorates experimental autoimmune encephalomyelitis by inhibiting Th1/Th17 response and cellular infiltration

Abstract: Simvastatin treatment promotes EAE clinical amelioration by inhibiting T cell proliferation and CNS infiltration by pathogenic Th1 and Th17 cells.

Cited by 27 publications

References 61 publications

Immune modulatory effects of statins

Immune modulatory effects of statins

Primary Progressive Multiple Sclerosis: Putting Together the Puzzle

Increased frequency of CD4+CD25high CD127low regulatory T cells in patients with multiple sclerosis

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