Atorvastatin Fails to Prevent the Development of Autoimmune Diabetes Despite Inhibition of Pathogenic β-Cell–Specific CD8 T-Cells

Lozanoska-Ochser, Biliana; Barone, Francesca; Pitzalis, Costantino; Peakman, Mark

doi:10.2337/diabetes.55.04.06.db05-1261

Cited by 20 publications

(10 citation statements)

References 28 publications

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“…Importantly, simvastatin does not limit renin release [11]. Secondly, vitamin D supplementation reduces the incidence of type 1 diabetes mellitus (pancreatic β cells express the VDR) – this is not seen in atorvastatin-treated individuals [12]. …”

Section: Discussionmentioning

confidence: 99%

Statins Do Not Affect Mineral Metabolism in Chronic Kidney Disease: A Retrospective Analysis

Ashman

Banerjee²,

Yaqoob³

2009

Nephron Clin Pract

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It has recently been proposed that statins act as vitamin D analogs in binding the ubiquitously expressed vitamin D receptor, accounting for the perceived pleiotropic effects of statins (a reduction in cancer risk, prevention of organ transplant rejection and autoimmune disease). Chronic kidney disease (CKD) offers a useful test of this hypothesis: serum 25-hydroxyvitamin D levels are insufficient (<75 nmol/l) in as many as 76% of patients with advanced CKD, associated with secondary hyperparathyroidism and reduced bone mineralization. Vitamin D suppresses parathyroid hormone (PTH) secretion in part through its action on the vitamin D receptor. If statins act as vitamin D analogs, they may then be able to suppress PTH secretion in CKD. We examined data on 714 vitamin D analog naïve patients with stage 3–4 CKD. 404 patients were treated with a statin indicated almost exclusively for primary prevention of coronary heart disease, and 310 patients were not. Both groups were similar in characteristics. Statins had no effect on the intact PTH concentration, the percentage of patients achieving K/DOQI™ PTH targets, or on calcium or phosphate concentrations. In patients with stage 3–4 CKD, statins had no effect on secondary hyperparathyroidism. If the hypothesis contending that statins act as vitamin D analogs to exert pleiotropic effects is true, this is of no clinical benefit in the prevention of secondary hyperparathyroidism in CKD.

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Section: Discussionmentioning

confidence: 99%

Statins Do Not Affect Mineral Metabolism in Chronic Kidney Disease: A Retrospective Analysis

Ashman

Banerjee²,

Yaqoob³

2009

Nephron Clin Pract

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“…They include (1) molecules that deplete T effector cells hopefully administered when islet-specific T cell response reaches its peak (i.e., anti-CD3, anti-CD2, and ATG (anti-thymocyte globulin)) [7][8][9], (2) molecules that induce islet-specific regulatory T cells ideally given when their number and/or their function was not able to keep under control the β cell immune-mediated damage (anti-CD3, CD4 + CD25 + regulatory T cell transfer, ATG, and low doses of IL-2) [10], (3) anti-inflammatory compounds given with a short and repeated scheduled timing in order to limit and/or stop β cell damage and the inflammatory milieu (anti-IL-1, anti-TNFα (anti-tumor necrosis factor-alpha), DiaPep277, and statin) [11][12][13][14], and (4) compounds that promote β cell regeneration and/or proliferation (GLP-1 (glucagon like peptide-1) receptor agonist and DPP4 (dipeptidyl peptidase 4) inhibitors) [15,16].…”

Section: Introductionmentioning

confidence: 99%

The CXCR1/2 Pathway: Involvement in Diabetes Pathophysiology and Potential Target for T1D Interventions

2015

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Although numerous chemokine/chemokine receptor pathways have been described to be implicated in the pathogenesis of type 1 diabetes (T1D), the CXCR1/2 axis has recently been proved to be crucial for leucocyte recruitment involved in insulitis and β cell damage. Multiple strategies blocking the CXCR1/2 pathway are available such as neutralizing antibodies, small molecules and peptide-derived inhibitors. They were firstly and widely used in cancer thanks to their anti-tumorigenic activity and only recently they were tested as a new interventional approach for T1D. As well, CXCR1/2 inhibition has been demonstrated to prevent inflammation- and autoimmunity-mediated damage of the pancreatic islets through inhibiting the migration of CXCR1/2-expressing cells. Among them, neutrophils, macrophages, and, although to a smaller extent, lymphoid cells are the main CXCR1/2-expressing cells. These results supported the active role of the innate immunity in the autoimmune process and opened new interventional approaches for the management of T1D.

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“…Statins have been indeed shown to prevent or reverse several Th1-mediated autoimmune conditions in mice, such as autoimmune encephalomyelitis [8], spontaneous systemic lupus erythematosus [9,10], autoimmune myocarditis [11] and autoimmune retinal disease [12] via suppression of Th1-type cytokine secretion through a mechanism involving primarily their inhibitory effects on isoprenoid biosynthesis [7,12]. Conversely, atorvastatin does not appear to affect the Th1/Th2 balance either in an experimental autoimmune uveitis mouse model [13] or in autoimmune diabetes in NOD mice [14].In addition to their direct effects on T cells, statins also modulate T-cell activation and differentiation by affecting APC. Statins inhibit APC maturation by reducing expression of CCR7, CD40, CD83 and CD86 on cytokine-stimulated DC [15] as well as IFN-g-inducible MHCII up-regulation on several cell types [16], thereby attenuating T-cell responses.…”

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confidence: 99%

Simvastatin impairs humoral and cell‐mediated immunity in mice by inhibiting lymphocyte homing, T‐cell activation and antigen cross‐presentation

et al. 2008

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Statins block the activity of HMG-CoA reductase, which catalyses the production of mevalonate, an intermediate in cholesterol biosynthesis, which is also a precursor of isoprenoids. In addition to lowering circulating cholesterol, these drugs display antiinflammatory and immunomodulatory activities in vitro; however, their effects on the development of adaptive immune responses in vivo, as well as the underlying mechanisms, are as yet largely unknown. Here we investigated the outcome of simvastatin treatment on a number of processes, which together orchestrate adaptive immunity to specific antigen. Simvastatin treatment resulted in a marked reduction of T and B cells in spleen, lymph nodes and peripheral blood in mice. This effect could be ascribed principally to an impairment of lymphocyte homing to secondary lymphoid organs. In addition, simvastatin was found to strongly inhibit T-cell responses to the MHCI restricted hen ovalbumin peptide antigen SIINFEKL and to impair ovalbumin uptake and cross-presentation by MHCI. Simvastatin also suppressed antibody responses to immunization with ovalbumin and delayed-type hypersensitivity to allergens. These activities could be largely accounted for by the simvastatin-dependent inhibition of HMG-CoA reductase. The data provide novel mechanistic insight into the activities of simvastatin in the highly complex context of the immune response.Key words: Apoptosis . Homing . Immune responses . Simvastatin IntroductionStatins are competitive inhibitors of HMG-CoA reductase, a major rate-limiting enzyme that controls HMG-CoA conversion to mevalonic acid in the cholesterol biosynthetic pathway. In addition to lowering circulating cholesterol, statins act as antiinflammatory and immunomodulatory agents [1]. These activities have been largely ascribed to their capacity to block isoprenoid production, and thereby to inhibit prenylation of small Ras superfamily GTPases, which are master regulators of cell activation and proliferation, cytoskeletal remodelling and membrane trafficking [2].Statins suppress T-cell activation both directly and by interfering with APC maturation and function. Statins inhibit T-cell activation, cell cycle progression and proliferation, as well as migration, both through an HMG-CoA-reductase-independent mechanism, involving allosteric inhibition of LFA-1 [3] and HMGCoA-reductase-dependent mechanisms, which rely on their capacity to inhibit prenylation of small GTPases [4,5]. Moreover, recent reports have provided evidence that some statins also 2832affect helper T-cell differentiation by promoting Th2 polarization and suppressing Th1 polarization both in vitro and in vivo [6,7]. This activity highlights statins as potential drugs in the treatment of diseases dominated by Th1 responses. Statins have been indeed shown to prevent or reverse several Th1-mediated autoimmune conditions in mice, such as autoimmune encephalomyelitis [8], spontaneous systemic lupus erythematosus [9,10], autoimmune myocarditis [11] and autoimmune retinal disease [12] via suppressio...

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Atorvastatin Fails to Prevent the Development of Autoimmune Diabetes Despite Inhibition of Pathogenic β-Cell–Specific CD8 T-Cells

Cited by 20 publications

References 28 publications

Statins Do Not Affect Mineral Metabolism in Chronic Kidney Disease: A Retrospective Analysis

Statins Do Not Affect Mineral Metabolism in Chronic Kidney Disease: A Retrospective Analysis

The CXCR1/2 Pathway: Involvement in Diabetes Pathophysiology and Potential Target for T1D Interventions

Simvastatin impairs humoral and cell‐mediated immunity in mice by inhibiting lymphocyte homing, T‐cell activation and antigen cross‐presentation

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