Treatment with rapamycin ameliorates clinical and histological signs of protracted relapsing experimental allergic encephalomyelitis in Dark Agouti rats and induces expansion of peripheral CD4+CD25+Foxp3+ regulatory T cells

Donia, Marco; Mangano, Katia; Amoroso, A; Mazzarino, María Clorinda; Imbesi, Rosa; Castrogiovanni, Paola; Coco, Marinella; Meroni, Pier Luigi; Nicoletti, Ferdinando

doi:10.1016/j.jaut.2009.06.003

Cited by 71 publications

(50 citation statements)

References 41 publications

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“…We chose to assess Th17 differentiation in vivo using the MOG 35-55 -induced model of EAE, since chemical and genetic approaches have established a role for mTORC1 in this model (13, 14, 19, 20). As expected, rapamycin treatment muted clinically apparent EAE symptoms and reduced the percentage of IL-17A + as well as IFNγ + cells in the spinal cord.…”

Section: Discussionmentioning

confidence: 99%

Context-Specific Function of S6K2 in Th Cell Differentiation

Pai

Walsh

Fruman

2016

The Journal of Immunology

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The mammalian target of rapamycin (mTOR) is essential for helper T cell proliferation and effector differentiation, making the mTOR signaling network an attractive immunomodulatory target for autoimmune related diseases. While direct targeting of mTOR-complex-1 (mTORC1) with rapamycin can provide clinical benefit, targeting downstream enzymes has potential to offer more selective immunosuppression. Here we evaluated p70 ribosomal protein S6 Kinase 2 (S6K2), a downstream effector of mTORC1, for its role in T cell function and autoimmunity. S6K2 is a direct substrate of mTORC1, with a potential role in Th17 differentiation suggested by biochemical studies. Using a genetic approach with S6K2 knockout mice, we found that S6K2 loss reduces Th17 skewing and increases Treg differentiation in vitro when cultured in RPMI media. However, S6K2 was dispensable for Th17 differentiation in IMDM media. In an in vivo EAE model in which rapamycin suppresses disease, S6K2 knockout mice did not exhibit differences in clinical score or Th17 differentiation. These results suggest that S6K2 is dispensable for Th17-driven autoimmunity and highlight how distinct experimental conditions can produce significantly different results in T cell differentiation.

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Section: Discussionmentioning

confidence: 99%

Context-Specific Function of S6K2 in Th Cell Differentiation

Pai

Walsh

Fruman

2016

The Journal of Immunology

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“…Although the precise mechanisms for the effects of rapamycin need to be elucidated, through mTOR inhibition, rapamycin can reduce the absorption of amino acids and glucose and dampen proinflammatory cytokines (including leptin) (42). This is interesting because rapamycin can improve disease curse and progression in EAE and type 1 diabetes by increasing regulatory T cell responses and dampening Th1/Th17 responses (43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

Leptin Modulates the Survival of Autoreactive CD4+ T Cells through the Nutrient/Energy-Sensing Mammalian Target of Rapamycin Signaling Pathway

Galgani

Procaccini

Rosa

et al. 2010

The Journal of Immunology

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Chronic inflammation can associate with autoreactive immune responses, including CD4+ T cell responses to self-Ags. In this paper, we show that the adipocyte-derived proinflammatory hormone leptin can affect the survival and proliferation of autoreactive CD4+ T cells in experimental autoimmune encephalomyelitis, an animal model of human multiple sclerosis. We found that myelin olygodendrocyte glycoprotein peptide 35–55 (MOG35–55)-specific CD4+ T cells from C57BL/6J wild-type mice could not transfer experimental autoimmune encephalomyelitis into leptin-deficient ob/ob mice. Such a finding was associated with a reduced proliferation of the transferred MOG35–55-reactive CD4+ T cells, which had a reduced degradation of the cyclin-dependent kinase inhibitor p27kip1 and ERK1/2 phosphorylation. The transferred cells displayed reduced Th1/Th17 responses and reduced delayed-type hypersensitivity. Moreover, MOG35–55-reactive CD4+ T cells in ob/ob mice underwent apoptosis that associated with a downmodulation of Bcl-2. Similar results were observed in transgenic AND-TCR- mice carrying a TCR specific for the pigeon cytochrome c 88–104 peptide. These molecular events reveal a reduced activity of the nutrient/energy-sensing AKT/mammalian target of rapamycin pathway, which can be restored in vivo by exogenous leptin replacement. These results may help to explain a link between chronic inflammation and autoimmune T cell reactivity.

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“…Indeed, rapamycin, through mTOR inhibition, is able to dampen the metabolic overload through reduction of absorption of amino acids and glucose, to dampen the level of a series of proinflammatory adipocytokines produced by adipocytes, including leptin [70,73]. This has also been confirmed in mouse models of autoimmunity, in which rapamycin by dampening Th1 and Th17 responses and increasing Treg cell responses improves disease curves and reduce disease progression, particularly in EAE and type 1 diabetes [74][75][76].…”

Section: Opinionmentioning

confidence: 91%