Oral simvastatin treatment in relapsing-remitting multiple sclerosis

Vollmer, Timothy; Key, L. Lyndon; Durkalski, Valerie; Tyor, William R.; Corboy, John R.; Marković-Pleše, Silva; Preiningerová, Jana Lízrová; Rizzo, Marco; Singh, Inderjit

doi:10.1016/s0140-6736(04)16205-3

Cited by 440 publications

(298 citation statements)

References 5 publications

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“…Fortunately, our work suggests that diseases arising from Treg migration defects are responsive to treatments that reestablish peripheral tolerance via recruitment to SLOs. In this regard, many autoimmune patients are receptive to drugs that are predicted to recruit (e.g., simvastatin) or retain (FTY720) (47,48) Tregs in SLOs (49)(50)(51)(52). If Treg migration defects are indeed proven to be a significant factor contributing to autoimmunity in the clinic, these findings would encourage the development of new therapeutics that redirect Treg trafficking to SLOs.…”

Section: Discussionmentioning

confidence: 99%

Peripheral tolerance can be modified by altering KLF2-regulated Treg migration

Kumar

Rabacal

Volanakis

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Tregs are essential for maintaining peripheral tolerance, and thus targeting these cells may aid in the treatment of autoimmunity and cancer by enhancing or reducing suppressive functions, respectively. Before these cells can be harnessed for therapeutic purposes, it is necessary to understand how they maintain tolerance under physiologically relevant conditions. We now report that transcription factor Kruppel-like factor 2 (KLF2) controls naive Treg migration patterns via regulation of homeostatic and inflammatory homing receptors, and that in its absence KLF2-deficient Tregs are unable to migrate efficiently to secondary lymphoid organs (SLOs). Diminished Treg trafficking to SLOs is sufficient to initiate autoimmunity, indicating that SLOs are a primary site for maintaining peripheral tolerance under homeostatic conditions. Disease severity correlates with impaired Treg recruitment to SLOs and, conversely, promotion of Tregs into these tissues can ameliorate autoimmunity. Moreover, stabilizing KLF2 expression within the Treg compartment enhances peripheral tolerance by diverting these suppressive cells from tertiary tissues into SLOs. Taken together, these results demonstrate that peripheral tolerance is enhanced or diminished through modulation of Treg trafficking to SLOs, a process that can be controlled by adjusting KLF2 protein levels.

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Section: Discussionmentioning

confidence: 99%

Peripheral tolerance can be modified by altering KLF2-regulated Treg migration

Kumar

Rabacal

Volanakis

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Clinical trials have demonstrated that statins can reduce morbidity in patients with multiple sclerosis [35,36]. Furthermore, in a 6 month, randomized, double-blind placebocontrolled clinical trial, patients with rheumatoid arthritis who received atorvastatin showed a reduction in disease activity [19].…”

Section: Clinical Trials With Statinsmentioning

confidence: 99%

Pleiotropic effects of statin therapy: molecular mechanisms and clinical results

Wang

Liu

Liao

2008

Trends in Molecular Medicine

537

394

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Statins inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which is required for cholesterol biosynthesis, and are beneficial in the primary and secondary prevention of cardiovascular disease. Most of the benefits of statin therapy are owing to the lowering of serum cholesterol levels. However, by inhibiting HMG-CoA reductase, statins can also inhibit the synthesis of isoprenoids, which are important lipid attachments for intracellular signaling molecules, such as Rho, Rac and Cdc42. Therefore, it is possible that statins might exert cholesterol-independent or 'pleiotropic' effects through direct inhibition of these small GTP-binding proteins. Recent studies have shown that statins might have important roles in diseases that are not mediated by cholesterol. Here, we review data from recent clinical trials that support the concept of statin pleiotropy and provide a rationale for their clinical importance. [6], have demonstrated the beneficial effects of statin therapy for primary and secondary prevention of cardiovascular disease. Because 60-70% of serum cholesterol is derived from hepatic synthesis and HMG-CoA reductase is the crucial, rate-limiting enzyme in the cholesterol biosynthetic pathway, inhibition of this enzyme by statins results in a dramatic reduction in circulating low-density lipoprotein (LDL)-cholesterol (Figure 1). In addition, reduction of LDL-cholesterol leads to upregulation of the LDL receptor and increased LDL clearance. The lowering of serum cholesterol levels is therefore thought to be the primary mechanism underlying the therapeutic benefits of statin therapy in cardiovascular disease [1]. Pleiotropy of statins: beyond cholesterol loweringStatins, however, might also exert cholesterol-independent or pleiotropic effects. By inhibiting the conversion of HMG-CoA to L-mevalonic acid, statins prevent the synthesis of important isoprenoids, such as farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP), which are precursors of cholesterol biosynthesis [7] (Figure 1). These intermediates serve as important lipid attachments for the post-translational modification of proteins, such as nuclear lamins, Ras, Rho, Rac and Rap [8]. These isoprenylated proteins constitute approximately 2% of total cellular proteins [9]. Protein isoprenylation (see Glossary) enables proper subcellular localization and trafficking of intracellular proteins. Given that isoprenylated proteins might

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“…In more recent trials, statins have begun to look promising. In 2004, a single-arm, open-label trial involving 30 individuals taking 80 mg of simvastatin per day for relapsing-remitting MS was reported (9). After 6 months of treatment, the number of gadoliniumenhancing brain lesions decreased by 44% (P Ͻ 0.0001) and the volume of the lesions decreased by 41% (P ϭ 0.0018) when compared with the lesions noted on pretreatment magnetic resonance imaging.…”

Section: Statin Trials In Human Inflammatory and Autoimmune Diseasesmentioning

confidence: 99%

“…However, studies also revealed that statins yield a larger mortality benefit than can be readily explained by their cholesterol-lowering effects alone, since their benefits occur too quickly to be explained by effects on atherosclerotic plaque (7), and are greater than lipid-lowering alone would predict (8). Additionally, statins appear to have beneficial effects on human diseases, such as multiple sclerosis (MS) (9) and osteoporosis (10), that have no direct association with cholesterol levels.…”

Section: Introductionmentioning

confidence: 99%