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Journal ArticleDOI

Neither T-helper type 2 nor Foxp3 + regulatory T cells are necessary for therapeutic benefit of atorvastatin in treatment of central nervous system autoimmunity

TL;DR: 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.

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Book ChapterDOI
01 Jan 2016
TL;DR: The role of innate immunity, both from CNS-resident cells and their products, and from circulating inflammatory cells and molecules which traverse the BBB are essential to “buy time,” inhibiting viral replication and dissemination, until the host can marshal an adaptive immune response.
Abstract: Innate immune responses to pathogens are evolutionarily ancient and are found in the most primitive organisms. These are highly conserved and are not pathogen-specific, but are in response to classes of molecular structures. Infections can be perceived both extracellularly and intracellularly by Pathogen Associated Molecular Patterns (PAMPs) and their host cell ligands, Pathogen Recognition Receptors (PRRs), among them, Toll-Like Receptors (TLRs). The innate immune response to infection includes the release of soluble preformed mediators, or synthesis of cytoplasmic enzymes, cytokines, chemokines, interferons (IFNs), lipid mediators, proteins of the complement cascade, neurotransmitters, nucleotides, and components of transcription factors (High Mobility Group B1, receptors for sex hormones/steroids). Directed cellular migration of parenchymal astrocytes and microglia, as well as recruitment across the blood brain barrier (BBB) of circulating neutrophils, natural killer, monocytes, macrophages, dendritic cells, and ultimately T lymphocytes to the site of infection are also hallmarks of innate responses to infections. These responding cells contribute their own secreted effector molecules and effector activities (such as phagocytosis). Distinct viruses are capable of infecting every cell type (endothelial cells, ependymal cells, perivascular macrophages and pericytes, astrocytes, microglia, oligodendrocytes, Schwann cells, and neurons) in the central nervous system (CNS). These CNS infections challenge the host with a different set of problems than do peripheral viral infections. Among the complications are (a) neurons that rarely express Class I or Class II Major Histocompatibility Complex (MHC) molecules and are thus not suitable targets for either CD4+ or CD8+ MHC-restricted T cells, (b) an enclosed volume that is constrained from swelling during inflammation, as well as poorly developed lymphatic drainage, and (c) the immunologic privilege of the CNS which leads to extremely limited immune surveillance for pathogens. Therefore, the role of innate immunity, both from CNS-resident cells and their products, and from circulating inflammatory cells and molecules which traverse the BBB are essential to “buy time,” inhibiting viral replication and dissemination, until the host can marshal an adaptive immune response. The immune responses are crucial for host survival from the infection. Consequently, successful pathogens, especially those that persist, have developed a wide variety of evasive approaches to limit the inhibition of replication. Many of these pathways are highlighted in individual chapters that precede this one. These evasive measures range from neutralizing host secreted molecules (cytokines and chemokines) with soluble receptors, encoding anti-inflammatory proteins in their genome, preventing signal transduction, blocking inhibition of protein synthesis, degradation of essential antiviral molecules, preventing apoptosis, and blockade of the nuclear pore complex. In this chapter, I will attempt to cover the breadth of the innate immune response to viral infection, but will also devote more space to generally under-considered aspects than to the well-known components. There are some caveats to consider, as most experiments have been performed in the murine model and not in man; further, conclusions from experiments using in vitro cultured cells (whether primary or established lines) may not reflect physiological conditions in an undisturbed CNS. Lastly, we now appreciate the complexities imposed on hosts by polymorphisms in genes of critical pathways, leading to increased susceptibility or resistance of that individual but not others.

4 citations


Cites background from "Neither T-helper type 2 nor Foxp3 +..."

  • ...In Langat virus and TBE infections, IFN is protective against fatal neurotropic disease (Weber et al. 2014a )....

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  • ...Statin treatment is benefi cial therapy in multiple sclerosis, not by inducing Th2 or Treg cells, but by inhibiting proliferation of infl ammatory T cell (Weber et al. 2014b )....

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Journal ArticleDOI
TL;DR: It seems that atorvastatin is not able to repair the deleterious effects of hypercholesterolemia on the immune system, and elevated levels of cholesterol along with the administration of atorVastatin tilt the Th1/Th2 balance in favor of Th2 and reduce T cell activation.
Abstract: Background and purpose: Many observations showed that hypercholesterolemia can disrupts immune response. Statin drugs that were used for the treatment of hypercholesterolemia patients can interfere in regulation of the immune response and cytokine secretion. The primary aim of the current study was to investigate the immune response among hypercholesterolemia patients, who were treatment-naive and healthy subjects. The secondary goal of the study was to determine whether atorvastatin can reverse the detrimental effect of hypercholesterolemia on the immune system. Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from 50 patients afflicted with hypercholesterolemia who were treatment-naive along with 50 sex- and age-matched hypercholesterolemia patients receiving atorvastatin and 50 sex- and age-matched healthy subjects. Quantitative PCR and ELISA methods were used for gene and protein expression analysis of T helper 1 (Th1) and Th2 related cytokines. Additionally, the expression of the cluster of differentiation (CD) markers on T, B, and NK cells were measured by flow cytometry method. Results: The results showed that hypercholesterolemia and atorvastatin downregulated the expression of Th1- related cytokines and elevated the levels of Th2-related cytokines. The expression of cell surface markers, CD25 and CD69, was significantly decreased in the treatment-naive, and atorvastatin groups. Conclusion: It seems that atorvastatin is not able to repair the deleterious effects of hypercholesterolemia on the immune system, and elevated levels of cholesterol along with the administration of atorvastatin tilt the Th1/Th2 balance in favor of Th2 and reduce T cell activation.

3 citations


Cites background from "Neither T-helper type 2 nor Foxp3 +..."

  • ...found that atorvastatin can boost the expression of Th2 cells [26,45]....

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Journal ArticleDOI
TL;DR: The therapeutic strategy to recover immune function through the restoration of impaired Tregs function with the mounting evidences regarding KRAS in autoimmune mediated disorder suggest as working hypothesis the direct targeting KRAS activation using cancer-derived small molecules may be clinically relevant.
Abstract: Ras signaling is involved in the development of autoimmunity in general. Multiple sclerosis (MS) is a T cell-mediated autoimmune disease of the central nervous system. It is widely recognized that a reduction of Foxp3+ regulatory T (Treg) cells is an immunological hallmark of MS, but the underlying mechanisms are unclear. In experimental autoimmune models, N-Ras and K-Ras inhibition triggers an anti-inflammatory effect up-regulating, via foxp3 elevation, the numbers and the functional suppressive properties of Tregs. Similarly, an increase in natural Tregs number during Experimental Autoimmune Encephalomyelitis (EAE) in R-RAS -/- mice results in attenuated disease. In humans, only KRAS GTPase isoform is involved in mechanism causing tolerance defects in rheumatoid arthritis (RA). T cells from these patients have increased transcription of KRAS (but not NRAS). RAS genes are major drivers in human cancers. Consequently, there has been considerable interest in developing anti-RAS inhibitors for cancer treatment. Despite efforts, no anti-RAS therapy has succeeded in the clinic. The major strategy that has so far reached the clinic aimed to inhibit activated Ras indirectly through blocking its post-translational modification and inducing its mis-localization. The disappointing clinical outcome of Farnesyl Transferase Inhibitors (FTIs) in cancers has decreased interest in these drugs. However, FTIs suppress EAE by downregulation of myelin-reactive activated T-lymphocytes and statins are currently studied in clinical trials for MS. However, no pharmacologic approaches to targeting Ras proteins directly have yet succeeded. The therapeutic strategy to recover immune function through the restoration of impaired Tregs function with the mounting evidences regarding KRAS in autoimmune mediated disorder (MS, SLE, RA, T1D) suggest as working hypothesis the direct targeting KRAS activation using cancer-derived small molecules may be clinically relevant. Abbreviations FTIs: Farnesyl Transferase Inhibitors; MS: Multiple Sclerosis; RRMS: Relapsing Remitting Multiple Sclerosis; PPMS: Primary Progressive Multiple Sclerosis; Tregs: regulatory T-cells; Foxp3: Forkhead box P3; EAE: Experimental Autoimmune Encephalomyelitis; T1D: Type 1 Diabete; SLE: Systemic Lupus Erythematosus; RA: Rheumatoid Arthritis; CNS: Central Nervous System; TMEV: Theiler's murine encephalomyelitis virus; FTS: farnesyl thiosalicylic acid; TCR: T-Cell Receptor; AIA: Adjuvant-induced Arthritis; EAN: experimental autoimmune neuritis; HVR: hypervariable region; HMG-CoA: 3-hydroxy-3-methylglutaryl coenzyme A reductase; PBMC: Peripheral Blood Mononuclear Cells.

3 citations

Book ChapterDOI
01 Jan 2019
TL;DR: This review critically analyze the current knowledge of the tolerance mechanisms involved in the regulation of MS and its animal model, experimental autoimmune encephalomyelitis.
Abstract: Multiple sclerosis (MS) afflicts genetically predisposed individuals and is associated with T lymphocyte-mediated damage to the myelin sheath of neurons in the central nervous system, resulting in severely impaired signal transmission. The mechanisms of the induction and manifestation of MS are not entirely understood. The control of autoimmune disorders is accomplished by both central tolerance in which autoreactive T lymphocytes are eliminated in the thymus and by tolerance mechanisms that operate in the periphery. Among the many mechanisms described, T regulatory (Treg) cells derived from the thymus (tTregs) and induced (iTregs) in the periphery as well as T regulatory type 1 cells (Tr1) are involved in many disease models. However, the precise details of the generation and perpetuation of these various Treg subsets and their relevance to the regulation of autoimmune diseases remain elusive. In this review, we critically analyze the current knowledge of the tolerance mechanisms involved in the regulation of MS and its animal model, experimental autoimmune encephalomyelitis.

3 citations

Journal ArticleDOI
TL;DR: Since SEB causes demyelination of spinal cord and increases the level of pro-inflammatory cytokine response, infiltration of T-lymphocytes and macrophages to CNS, it may exacerbate the clinical signs of EAE in mice and multiple sclerosis in human.

1 citations

References
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Journal ArticleDOI
07 Nov 2002-Nature
TL;DR: It is shown that oral atorvastatin prevented or reversed chronic and relapsing paralysis and has pleiotropic immunomodulatory effects involving both APC and T-cell compartments.
Abstract: Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, which are approved for cholesterol reduction, may also be beneficial in the treatment of inflammatory diseases. Atorvastatin (Lipitor) was tested in chronic and relapsing experimental autoimmune encephalomyelitis, a CD4(+) Th1-mediated central nervous system (CNS) demyelinating disease model of multiple sclerosis. Here we show that oral atorvastatin prevented or reversed chronic and relapsing paralysis. Atorvastatin induced STAT6 phosphorylation and secretion of Th2 cytokines (interleukin (IL)-4, IL-5 and IL-10) and transforming growth factor (TGF)-beta. Conversely, STAT4 phosphorylation was inhibited and secretion of Th1 cytokines (IL-2, IL-12, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha) was suppressed. Atorvastatin promoted differentiation of Th0 cells into Th2 cells. In adoptive transfer, these Th2 cells protected recipient mice from EAE induction. Atorvastatin reduced CNS infiltration and major histocompatibility complex (MHC) class II expression. Treatment of microglia inhibited IFN-gamma-inducible transcription at multiple MHC class II transactivator (CIITA) promoters and suppressed class II upregulation. Atorvastatin suppressed IFN-gamma-inducible expression of CD40, CD80 and CD86 co-stimulatory molecules. l-Mevalonate, the product of HMG-CoA reductase, reversed atorvastatin's effects on antigen-presenting cells (APC) and T cells. Atorvastatin treatment of either APC or T cells suppressed antigen-specific T-cell activation. Thus, atorvastatin has pleiotropic immunomodulatory effects involving both APC and T-cell compartments. Statins may be beneficial for multiple sclerosis and other Th1-mediated autoimmune diseases.

1,082 citations


"Neither T-helper type 2 nor Foxp3 +..." refers background or methods in this paper

  • ...myocarditis [5,6], experimental systemic lupus erythematosus [7] and experimental autoimmune encephalomyelitis (EAE) [2,8-10], the animal model for multiple sclerosis (MS)....

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  • ...These doses have been previously shown to prevent EAE [2]....

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  • ...Besides their metabolic properties, statins attracted interest for their immunomodulatory potential [2]....

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  • ...We observed that in vivo AT treatment during EAE inhibited proliferation of myelin-specific T cells upon restimulation ex vivo [2,8] (Figure 4a), suggesting that these myelin-reactive cells expanded less in AT-treated mice post vaccination....

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  • ...) was brought into suspension in phosphate-buffered saline as described previously [2]....

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Journal ArticleDOI
01 Mar 2011-Brain
TL;DR: The ability of dimethylfumarate to activate nuclear factor (erythroid-derived 2)-related factor 2 may offer a novel cytoprotective modality that further augments the natural antioxidant responses in multiple sclerosis tissue and is not yet targeted by other multiple sclerosis therapies.
Abstract: Inflammation and oxidative stress are thought to promote tissue damage in multiple sclerosis. Thus, novel therapeutics enhancing cellular resistance to free radicals could prove useful for multiple sclerosis treatment. BG00012 is an oral formulation of dimethylfumarate. In a phase II multiple sclerosis trial, BG00012 demonstrated beneficial effects on relapse rate and magnetic resonance imaging markers indicative of inflammation as well as axonal destruction. First we have studied effects of dimethylfumarate on the disease course, central nervous system, tissue integrity and the molecular mechanism of action in an animal model of chronic multiple sclerosis: myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis in C57BL/6 mice. In the chronic phase of experimental autoimmune encephalomyelitis, preventive or therapeutic application of dimethylfumarate ameliorated the disease course and improved preservation of myelin, axons and neurons. In vitro, the application of fumarates increased murine neuronal survival and protected human or rodent astrocytes against oxidative stress. Application of dimethylfumarate led to stabilization of the transcription factor nuclear factor (erythroid-derived 2)-related factor 2, activation of nuclear factor (erythroid-derived 2)-related factor 2-dependent transcriptional activity and accumulation of NADP(H) quinoline oxidoreductase-1 as a prototypical target gene. Furthermore, the immediate metabolite of dimethylfumarate, monomethylfumarate, leads to direct modification of the inhibitor of nuclear factor (erythroid-derived 2)-related factor 2, Kelch-like ECH-associated protein 1, at cysteine residue 151. In turn, increased levels of nuclear factor (erythroid-derived 2)-related factor 2 and reduced protein nitrosylation were detected in the central nervous sytem of dimethylfumarate-treated mice. Nuclear factor (erythroid-derived 2)-related factor 2 was also upregulated in the spinal cord of autopsy specimens from untreated patients with multiple sclerosis. In dimethylfumarate-treated mice suffering from experimental autoimmune encephalomyelitis, increased immunoreactivity for nuclear factor (erythroid-derived 2)-related factor 2 was detected by confocal microscopy in neurons of the motor cortex and the brainstem as well as in oligodendrocytes and astrocytes. In mice deficient for nuclear factor (erythroid-derived 2)-related factor 2 on the same genetic background, the dimethylfumarate mediated beneficial effects on clinical course, axon preservation and astrocyte activation were almost completely abolished thus proving the functional relevance of this transcription factor for the neuroprotective mechanism of action. We conclude that the ability of dimethylfumarate to activate nuclear factor (erythroid-derived 2)-related factor 2 may offer a novel cytoprotective modality that further augments the natural antioxidant responses in multiple sclerosis tissue and is not yet targeted by other multiple sclerosis therapies.

936 citations


"Neither T-helper type 2 nor Foxp3 +..." refers background in this paper

  • ...factor (Nrf2) pathway [49,50], it also exerts anti-...

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Journal ArticleDOI
TL;DR: Investigation of use of oral simvastatin in 30 individuals with relapsing-remitting multiple sclerosis found it to inhibit inflammatory components of multiple sclerosis that lead to neurological disability.

475 citations


"Neither T-helper type 2 nor Foxp3 +..." refers background in this paper

  • ...How does this new information impact the potential use of statins in MS [42]? At first glance, nonspecific inhibition of proinflammatory T-cell differentiation in MS may be viewed less advantageously than the active induction of an anti-inflammatory T-cell phenotype [17,18,43]....

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  • ...In the first placebo-controlled trial testing a statin as monotherapy in MS, atorvastatin (AT) significantly reduced the risk of developing new magnetic resonance imaging demyelinating lesions in patients with clinical isolated syndromes, but did not meet its primary endpoint that included reduction in conversion to clinically definite MS [17,18]....

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Journal ArticleDOI
01 Aug 2001-Immunity
TL;DR: Reporter T cells primed under Th2 conditions showed sensitive and faithful EGFP expression and maintained endogenous IL-4, and reporter expression demonstrated the evolution of type 2 immunity from tissue lymphocytes and thence to lymph node CD4(+) T cells, which subsequently migrated into tissue.

439 citations

Journal ArticleDOI
TL;DR: Adoptive transfer of type II monocytes reversed EAE, suppressed TH17 cell development and promoted both TH2 differentiation and expansion of Treg cells in recipient mice, identifying a central role for these cells in T cell immune modulation of autoimmunity.
Abstract: Treatment with glatiramer acetate (GA, copolymer-1, Copaxone), a drug approved for multiple sclerosis (MS), in a mouse model promoted development of anti-inflammatory type II monocytes, characterized by increased secretion of interleukin (IL)-10 and transforming growth factor (TGF)-beta, and decreased production of IL-12 and tumor necrosis factor (TNF). This anti-inflammatory cytokine shift was associated with reduced STAT-1 signaling. Type II monocytes directed differentiation of T(H)2 cells and CD4+CD25+FoxP3+ regulatory T cells (T(reg)) independent of antigen specificity. Type II monocyte-induced regulatory T cells specific for a foreign antigen ameliorated experimental autoimmune encephalomyelitis (EAE), indicating that neither GA specificity nor recognition of self-antigen was required for their therapeutic effect. Adoptive transfer of type II monocytes reversed EAE, suppressed T(H)17 cell development and promoted both T(H)2 differentiation and expansion of T(reg) cells in recipient mice. This demonstration of adoptive immunotherapy by type II monocytes identifies a central role for these cells in T cell immune modulation of autoimmunity.

436 citations


"Neither T-helper type 2 nor Foxp3 +..." refers background or result in this paper

  • ...(b) The frequency of CD4+CD25+FoxP3+ regulatory T cells (Tregs) was evaluated by fluorescence-activated cell sorting....

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  • ...However, it was not associated with an increase in CD4+CD25+FoxP3+ Tregs in either STAT6-deficient or wild-type mice....

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  • ...A potential increase in Tregs is therefore unlikely to significantly contribute to the anti-inflammatory effect of statins in CNS autoimmune disease....

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  • ...Induction of CD4+CD25+FoxP3+ Tregs was evaluated using a FACS staining kit by eBioscience....

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  • ...Whether statins solely inhibit encephalitogenic T-cell differentiation or whether they may actively induce regulatory T-cell populations such as Th2 cells or Foxp3+ Tregs, considered a desirable goal in treatment of MS, thus remains to be investigated....

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