Browsing by keyword "rapamycin"
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Rapamycin Improves the Response of Effector and Memory CD8(+) T Cells Induced by Immunization With ASP2 of Trypanosoma cruziDeficiency in memory formation and increased immunosenescence are pivotal features of Trypanosoma cruzi infection proposed to play a role in parasite persistence and disease development. The vaccination protocol that consists in a prime with plasmid DNA followed by the boost with a deficient recombinant human adenovirus type 5, both carrying the ASP2 gene of T. cruzi, is a powerful strategy to elicit effector memory CD8(+) T-cells against this parasite. In virus infections, the inhibition of mTOR, a kinase involved in several biological processes, improves the response of memory CD8(+) T-cells. Therefore, our aim was to assess the role of rapamycin, the pharmacological inhibitor of mTOR, in CD8(+) T response against T. cruzi induced by heterologous prime-boost vaccine. For this purpose, C57BL/6 or A/Sn mice were immunized and daily treated with rapamycin for 34 days. CD8(+) T-cells response was evaluated by immunophenotyping, intracellular staining, ELISpot assay and in vivo cytotoxicity. In comparison with vehicle-injection, rapamycin administration during immunization enhanced the frequency of ASP2-specific CD8(+) T-cells and the percentage of the polyfunctional population, which degranulated (CD107a(+)) and secreted both interferon gamma (IFNgamma) and tumor necrosis factor (TNF). The beneficial effects were long-lasting and could be detected 95 days after priming. Moreover, the effects were detected in mice immunized with ten-fold lower doses of plasmid/adenovirus. Additionally, the highly susceptible to T. cruzi infection A/Sn mice, when immunized with low vaccine doses, treated with rapamycin, and challenged with trypomastigote forms of the Y strain showed a survival rate of 100%, compared with 42% in vehicle-injected group. Trying to shed light on the biological mechanisms involved in these beneficial effects on CD8(+) T-cells by mTOR inhibition after immunization, we showed that in vivo proliferation was higher after rapamycin treatment compared with vehicle-injected group. Taken together, our data provide a new approach to vaccine development against intracellular parasites, placing the mTOR inhibitor rapamycin as an adjuvant to improve effective CD8(+) T-cell response.
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Reprogramming of mTOR Signaling by Perinatal Exposure to Brominated Flame RetardantMammalian target of rapamycin (mTOR), also known as mechanistic target of rapamycin, is a known metabolic master-switch. In conditions of starvation, mTOR suppresses biosynthetic programs and increases the recycling of proteins and organelles. Upon stimulation by nutrients and growth factors, however, mTOR causes activation of biosynthesis and suppression of autophagy. The mTOR-centered molecular pathway is a major pathway of growth regulation and metabolism, linked to aging and the development of cancer, obesity, type 2 diabetes, neurodevelopmental and neurodegenerative diseases. Currently, the role of environmental factors in the modulation of the mTOR pathway remains largely unknown. The present study suggests that perinatal exposure to environmentally-relevant doses of polybrominated diphenyl ethers (PBDEs), a group of ubiquitous flame-retardants, results in long-lasting reprogramming of the mTOR pathway in mouse liver. This reprogramming includes suppression of mTORC1 and mTORC2 activity, accompanied by coordinated up-regulation of protein synthesis machinery and increased concentrations of circulating IGF-1. Further, experiments with MCF-7 breast cancer cells demonstrate that exposure to PBDEs results in fast induction of the REDD1/DDIT4 gene – a potent suppressor of mTORC1. This data indicates that the response of liver tissue to PBDE exposure during this critical developmental window is a dynamic process, and is likely triggered via a REDD1-dependent mechanism, ultimately resulting in long-lasting changes in the metabolic profile of the tissue. This study suggests that environmental exposures to brominated flame retardants may have profound and long-term effects on the central regulation hub of metabolic health, and may be implicated in the pathogenesis of the most relevant diseases of modern society.
