Treatment of Relapsing Paralysis in Experimental Encephalomyelitis by Targeting Th1 Cells through Atorvastatin
17 Mar 2003-Journal of Experimental Medicine (The Rockefeller University Press)-Vol. 197, Iss: 6, pp 725-733
TL;DR: It is demonstrated that both subcutaneous and oral administration of atorvastatin inhibit the development of actively induced chronic experimental autoimmune encephalomyelitis in SJL/J mice and significantly reduce the inflammatory infiltration into the central nervous system (CNS).
Abstract: Statins, known as inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, exhibit numerous functions related to inflammation, such as MHC class II down-regulation, interference with T cell adhesion, and induction of apoptosis. Here we demonstrate that both subcutaneous and oral administration of atorvastatin inhibit the development of actively induced chronic experimental autoimmune encephalomyelitis in SJL/J mice and significantly reduce the inflammatory infiltration into the central nervous system (CNS). When treatment was started after disease onset, atorvastatin reduced the incidence of relapses and protected from the development of further disability. Both the reduced autoreactive T cell response measured by proliferation toward the encephalitogenic peptide PLP139–151 and the cytokine profile indicate a potent blockade of T helper cell type 1 immune response. In in vitro assays atorvastatin not only inhibited antigen-specific responses, but also decreased T cell proliferation mediated by direct TCR engagement independently of MHC class II and LFA-1. Inhibition of proliferation was not due to apoptosis induction, but linked to a negative regulation on cell cycle progression. However, early T cell activation was unaffected, as reflected by unaltered calcium fluxes. Thus, our results provide evidence for a beneficial role of statins in the treatment of autoimmune attack on the CNS.
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TL;DR: Recent studies indicate that some of the cholesterol-independent or "pleiotropic" effects of statins involve improving endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response.
Abstract: ▪ Abstract Statins are potent inhibitors of cholesterol biosynthesis. In clinical trials, statins are beneficial in the primary and secondary prevention of coronary heart disease. However, the over...
1,712 citations
TL;DR: Critically discuss models of experimental autoimmune encephalomyelitis that reproduce specific features of the histopathology and neurobiology of multiple sclerosis and their shortcomings as tools to investigate emerging therapeutic approaches.
Abstract: In view of disease heterogeneity of multiple sclerosis and limited access to ex vivo specimens, different approaches must be undertaken to better understand disease pathogenesis and new therapeutic challenges. Here, we critically discuss models of experimental autoimmune encephalomyelitis (EAE) that reproduce specific features of the histopathology and neurobiology of multiple sclerosis and their shortcomings as tools to investigate emerging therapeutic approaches. By using EAE models we have understood mechanisms of T-cell mediated immune damage of the CNS, and the associated effector cascade of innate immunity. Also, the importance of humoral components of the immune system for demyelination has been delineated in EAE, before it was applied therapeutically to subtypes of multiple sclerosis. Yet, similar to multiple sclerosis, EAE is also heterogeneous and influenced by the selected autoantigen, species and the genetic background. In particular, the relevance of cytotoxic CD8 T cells for human multiple sclerosis has been underestimated in most EAE models, and no EAE model exists that mimics primary progressive disease courses of multiple sclerosis. Seventy years after the first description of EAE and the publication of >7000 articles, we are aware of the obvious limitations of EAE as a model of multiple sclerosis, but feel strongly that when used appropriately it will continue to provide a crucial tool for improving our understanding and treatment of this devastating disease.
995 citations
Cites background from "Treatment of Relapsing Paralysis in..."
..., 2002) were soon followed by work pointing at microglial activation by lipid degradation products, downregulated by statin activity (Aktas et al., 2003)....
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...The first experimental studies from Dr Steinman’s group (Youssef et al., 2002) were soon followed by work pointing at microglial activation by lipid degradation products, downregulated by statin activity (Aktas et al., 2003)....
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TL;DR: The effect of statin therapy on immune function, and how this relates to the pathogenesis of autoimmune disease, is reviewed alongside current opinion of what the key biological targets of statins are.
Abstract: Statins have been prescribed extensively for their cholesterol-lowering properties and efficacy in cardiovascular disease. However, compelling evidence now exists that statins also have extensive immunomodulatory properties that operate independently of lipid lowering. Consequently, much attention has been directed towards their potential as therapeutic agents for the treatment of autoimmune disease. Modulation of post-translational protein prenylation seems to be a key mechanism by which statins alter immune function. In this Review, the effect of statin therapy on immune function, and how this relates to the pathogenesis of autoimmune disease, is reviewed alongside current opinion of what the key biological targets of statins are.
602 citations
TL;DR: Controversy persists regarding the (clinical) relevance of these potential non–LDL-lowering “pleiotropic” functions of statins, but this overview addresses the controversy by reviewing in vitro and in vivo evidence regarding statins as antiinflammatory agents.
Abstract: According to traditional thinking, atherosclerosis results from passive lipid deposition in the vascular wall. Thus, therapies predominantly targeted lipid metabolism. The contemporary view of atherosclerosis, however, has broadened to include an active and complex role for inflammation, orchestrated in part by mediators of the immune system. This recognition prompted the question of whether antiinflammatory interventions might provide a novel avenue for the treatment of atherosclerosis. Uncertainties about the type of antiinflammatory regimen and appropriate patient selection currently hamper clinical investigation. Yet cardiovascular scientists have begun to address these questions at the bench, in experimental models, and indirectly in humans. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A HMG-CoA reductase (statins) have emerged as promising tools with dual functions. Originally designed to target elevated lipids, the "traditional" cause of atherosclerosis, statins might also confer cardiovascular benefit by directly or indirectly modulating the inflammatory component of this prevalent disease. Yet controversy persists regarding the (clinical) relevance of these potential non-LDL-lowering "pleiotropic" functions of statins. This overview addresses the controversy by reviewing in vitro and in vivo evidence regarding statins as antiinflammatory agents.
510 citations
TL;DR: The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular reactive oxygen species (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive as discussed by the authors.
Abstract: The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular 'reactive oxygen species' (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation.
452 citations
References
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TL;DR: In this prospective trial, pravastatin reduced CRP levels at both 12 and 24 weeks in a largely LDL-C-independent manner, providing evidence that statins may have anti-inflammatory effects in addition to lipid-lowering effects.
Abstract: ContextPlasma levels of the inflammatory biomarker C-reactive protein (CRP)
predict cardiovascular risk, and retrospective studies suggest that 3-hydroxy-3-methylglutaryl
coenzyme A reductase inhibitors (statins) may lower CRP in a manner largely
independent of low-density lipoprotein cholesterol (LDL-C). However, prospective
trial data directly evaluating this anti-inflammatory effect of statins are
not available.ObjectiveTo test the hypothesis that pravastatin has anti-inflammatory effects
as evidenced by CRP reduction.Design, Setting, and ParticipantsCommunity-based, prospective, randomized, double-blind trial including
1702 men and women with no prior history of cardiovascular disease (primary
prevention cohort) and open-label study including 1182 patients with known
cardiovascular disease (secondary prevention cohort) who provided at least
baseline and 12-week blood samples. The study was conducted in US office-based
practices from February to December 2000.InterventionsParticipants in the double-blind primary prevention trial were randomly
assigned to receive 40 mg/d of pravastatin (n = 865) or placebo (n = 837)
for 24 weeks. Participants in the secondary prevention cohort received 40
mg/d of open-label pravastatin for 24 weeks.Main Outcome MeasureChange in CRP levels from baseline to 24 weeks.ResultsIn the primary prevention trial, compared with placebo, pravastatin
reduced median CRP levels by 16.9% (P<.001) at
24 weeks, reflecting a decrease of 0.02 mg/dL in the pravastatin group while
no change in CRP levels was observed in the placebo group. This effect was
seen as early as 12 weeks (median reduction in CRP with pravastatin, 14.7%; P<.001) and was present among all prespecified subgroups
according to sex, age, smoking status, body mass index, baseline lipid levels,
presence of diabetes, and use of aspirin or hormone replacement therapy. No
significant association was observed between baseline CRP and baseline LDL-C
levels, end-of-study CRP and end-of-study LDL-C levels, or change in CRP and
change in LDL-C levels over time. In linear regression analyses, the only
significant predictors of change in CRP on a log scale were randomized pravastatin
allocation and baseline CRP levels (P<.001 for
both). Similar reductions in CRP levels were observed at 12 weeks (−14.3%)
and 24 weeks (−13.1%) in the secondary prevention cohort treated with
pravastatin (P<.005 for both).ConclusionsIn this prospective trial, pravastatin reduced CRP levels at both 12
and 24 weeks in a largely LDL-C–independent manner. These data provide
evidence that statins may have anti-inflammatory effects in addition to lipid-lowering
effects.
1,573 citations
"Treatment of Relapsing Paralysis in..." refers background in this paper
...Two independent studies have shown that both pravastatin and lovastatin reduce serum concentrations of C-reactive protein, a marker of inflammation, by 15% (2, 3)....
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TL;DR: As expected, lovastatin was effective in preventing coronary events in participants whose base-line ratio of total cholesterol to high-de...
Abstract: Background Elevated levels of C-reactive protein, even in the absence of hyperlipidemia, are associated with an increased risk of coronary events. Statin therapy reduces the level of C-reactive protein independently of its effect on lipid levels. We hypothesized that statins might prevent coronary events in persons with elevated C-reactive protein levels who did not have overt hyperlipidemia. Methods The level of C-reactive protein was measured at base line and after one year in 5742 participants in a five-year randomized trial of lovastatin for the primary prevention of acute coronary events. Results The rates of coronary events increased significantly with increases in the base-line levels of C-reactive protein. Lovastatin therapy reduced the C-reactive protein level by 14.8 percent (P<0.001), an effect not explained by lovastatin-induced changes in the lipid profile. As expected, lovastatin was effective in preventing coronary events in participants whose base-line ratio of total cholesterol to high-de...
1,444 citations
TL;DR: It is shown that statins act as direct inhibitors of induction of MHC-II expression by IFN-γ and thus as repressors of M HC-II-mediated T-cell activation, providing a new type of immunomodulation.
Abstract: Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, or statins, are effective lipid-lowering agents, extensively used in medical practice. Statins have never been shown to be involved in the immune response, although a report has indicated a better outcome of cardiac transplantation in patients under Pravastatin therapy. Major histocompatibility complex class II (MHC-II) molecules are directly involved in the activation of T lymphocytes and in the control of the immune response. Whereas only a limited number of specialized cell types express MHC-II constitutively, numerous other cells become MHC-II positive upon induction by interferon gamma (IFN-gamma). This complex regulation is under the control of the transactivator CIITA (refs 6,7). Here we show that statins act as direct inhibitors of induction of MHC-II expression by IFN-gamma and thus as repressors of MHC-II-mediated T-cell activation. This effect of statins is due to inhibition of the inducible promoter IV of the transactivator CIITA and is observed in several cell types, including primary human endothelial cells (ECs) and monocyte-macrophages (Mstraight phi). It is of note that this inhibition is specific for inducible MHC-II expression and does not concern constitutive expression of CIITA and MHC-II. In repressing induction of MHC-II, and subsequent T-lymphocyte activation, statins therefore provide a new type of immunomodulation. This unexpected effect provides a scientific rationale for using statins as immunosuppressors, not only in organ transplantation but in numerous other pathologies as well.
1,345 citations
"Treatment of Relapsing Paralysis in..." refers background in this paper
...This points to further pathways of immunomodulatory statin function in addition to those involving a reduced MHC class II upregulation by inhibition of the inducible promoter IV of the transactivator CIITA (5), and the blockade of LFA-1– Figure 2....
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...demonstrated in an initial report that statins inhibit the IFN- –induced expression of MHC class II on most APCs, including B cells and macrophages (5)....
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...Because atorvastatin may confer its immunomodulatory effects, both dependent on (5) and independent of (6) inhibition of HMG-CoA reductase, it was important to clarify whether the direct T cell–targeted antiproliferative effect reported here is mediated by the HMG-CoA reductase pathway....
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...This points to further pathways of immunomodulatory statin function in addition to those involving a reduced MHC class II upregulation by inhibition of the inducible promoter IV of the transactivator CIITA (5), and the blockade of LFA-1– Figure 2....
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TL;DR: After cardiac transplantation, pravastatin had beneficial effects on cholesterol levels, the incidence of rejection causing hemodynamic compromise, one-year survival, andThe incidence of coronary vasculopathy.
Abstract: Background Hypercholesterolemia is common after cardiac transplantation and may contribute to the development of coronary vasculopathy. Pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been shown to be effective and safe in lowering cholesterol levels after cardiac transplantation. Cell-culture studies using inhibitors of HMG-CoA reductase have suggested an immunosuppressive effect. Methods Early after transplantation, we randomly assigned consecutive patients to receive either pravastatin (47 patients) or no HMG-CoA reductase inhibitor (50 patients). Results Twelve months after transplantation, the pravastatin group had lower mean (±SD) cholesterol levels than the control group (193±36 vs. 248±49 mg per deciliter, P<0.001), less frequent cardiac rejection accompanied by hemodynamic compromise (3 vs. 14 patients, P = 0.005), better survival (94 percent vs. 78 percent, P = 0.025), and a lower incidence of coronary vasculopathy in the transplant as determined by angiog...
1,261 citations
"Treatment of Relapsing Paralysis in..." refers background in this paper
...For example, pravastatin improves survival and lowers the incidence of acute rejection after heart transplantation (4)....
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TL;DR: Statin therapy may be effective in the primary prevention of coronary events among subjects with relatively low lipid levels but with elevated levels of C-reactive protein.
Abstract: BACKGROUND
Elevated levels of C-reactive protein, even in the absence of hyperlipidemia, are associated with an increased risk of coronary events. Statin therapy reduces the level of C-reactive protein independently of its effect on lipid levels. We hypothesized that statins might prevent coronary events in persons with elevated C-reactive protein levels who did not have overt hyperlipidemia.
METHODS
The level of C-reactive protein was measured at base line and after one year in 5742 participants in a five-year randomized trial of lovastatin for the primary prevention of acute coronary events.
RESULTS
The rates of coronary events increased significantly with increases in the base-line levels of C-reactive protein. Lovastatin therapy reduced the C-reactive protein level by 14.8 percent (P<0.001), an effect not explained by lovastatin-induced changes in the lipid profile. As expected, lovastatin was effective in preventing coronary events in participants whose base-line ratio of total cholesterol to high-density lipoprotein (HDL) cholesterol was higher than the median ratio, regardless of the level of C-reactive protein (number needed to treat for five years to prevent 1 event, 47; P=0.005). However, lovastatin was also effective among those with a ratio of total to HDL cholesterol that was lower than the median and a C-reactive protein level higher than the median (number needed to treat, 43; P=0.02). In contrast, lovastatin was ineffective among participants with a ratio of total to HDL cholesterol and a C-reactive protein level that were both lower than the median (number needed to treat, 983; P=0.80).
CONCLUSIONS
Statin therapy may be effective in the primary prevention of coronary events among subjects with relatively low lipid levels but with elevated levels of C-reactive protein.
1,207 citations
"Treatment of Relapsing Paralysis in..." refers background in this paper
...Two independent studies have shown that both pravastatin and lovastatin reduce serum concentrations of C-reactive protein, a marker of inflammation, by 15% (2, 3)....
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