Dataset Information

Efficacy and safety assessment of a TRAF6-targeted nanoimmunotherapy in atherosclerotic mice and non-human primates.

ABSTRACT: Macrophage accumulation in atherosclerosis is directly linked to the destabilization and rupture of plaque, causing acute atherothrombotic events. Circulating monocytes enter the plaque and differentiate into macrophages, where they are activated by CD4+ T lymphocytes through CD40-CD40 ligand signalling. Here, we report the development and multiparametric evaluation of a nanoimmunotherapy that moderates CD40-CD40 ligand signalling in monocytes and macrophages by blocking the interaction between CD40 and tumour necrosis factor receptor-associated factor 6 (TRAF6). We evaluated the biodistribution characteristics of the nanoimmunotherapy in apolipoprotein E-deficient (Apoe-/-) mice and in non-human primates by in vivo positron-emission tomography imaging. In Apoe-/- mice, a 1-week nanoimmunotherapy treatment regimen achieved significant anti-inflammatory effects, which was due to the impaired migration capacity of monocytes, as established by a transcriptome analysis. The rapid reduction of plaque inflammation by the TRAF6-targeted nanoimmunotherapy and its favourable toxicity profiles in both mice and non-human primates highlights the translational potential of this strategy for the treatment of atherosclerosis.

SUBMITTER: Lameijer M

PROVIDER: S-EPMC6447057 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Efficacy and safety assessment of a TRAF6-targeted nanoimmunotherapy in atherosclerotic mice and non-human primates.

Lameijer Marnix M Binderup Tina T van Leent Mandy M T MMT Senders Max L ML Fay Francois F Malkus Joost J Sanchez-Gaytan Brenda L BL Teunissen Abraham J P AJP Karakatsanis Nicolas N Robson Philip P Zhou Xianxiao X Ye Yuxiang Y Wojtkiewicz Gregory G Tang Jun J Seijkens Tom T P TTP Kroon Jeffrey J Stroes Erik S G ESG Kjaer Andreas A Ochando Jordi J Reiner Thomas T Pérez-Medina Carlos C Calcagno Claudia C Fisher Edward A EA Zhang Bin B Temel Ryan E RE Swirski Filip K FK Nahrendorf Matthias M Fayad Zahi A ZA Lutgens Esther E Mulder Willem J M WJM Duivenvoorden Raphaël R

Nature biomedical engineering 20180416 5

Macrophage accumulation in atherosclerosis is directly linked to the destabilization and rupture of plaque, causing acute atherothrombotic events. Circulating monocytes enter the plaque and differentiate into macrophages, where they are activated by CD4<sup>+</sup> T lymphocytes through CD40-CD40 ligand signalling. Here, we report the development and multiparametric evaluation of a nanoimmunotherapy that moderates CD40-CD40 ligand signalling in monocytes and macrophages by blocking the interacti ...[more]

PMID: 30936448

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Project description:The most widely used animal models to develop sleep-disorder drugs are rodents, particularly rats and mice. However, unlike humans, these rodents are nocturnal. Thus, diurnal non-human primates represent a valuable and more translational animal model to study sleep. Although sleep-disorder drugs have been screened in non-human primates, the use of a telemetry system is not a desirable method for a rapid drug efficacy assessment system because of the need for expensive equipment, complicated surgery, and the long time before results can be obtained from analysis by inspection. Locomotor activity has traditionally been used as an indicator of the effects of drugs, genes, and disease models. The Nano-Tag, a new device for analyzing activity after an easy implantation surgery, measures locomotor activity without expensive equipment and the need for inspection for data processing, and the overall cost is much lower than that of a telemetry system. In this study, we compared the data obtained from polysomnography and on locomotor activity in telemetry transmitter-embedded cynomolgus monkeys by implanting the Nano-Tag subcutaneously in the forehead and administering sleep-disorder drugs to confirm if sleep-wake states could be measured using the Nano-Tag. When we compared the changes in awake time per unit time measured using polysomnography and locomotor activity counts per unit time measured using the Nano-Tag, cynomolgus monkeys exhibited a diurnal preference, and the correlation coefficients were positive during the 24-h period. Additionally, the correlation coefficients during the 12-h dark period were positive when the hypersomnia treatment drug modafinil was administered. The correlation coefficients during the 12-h light period were also positive when the insomnia treatment drug triazolam was administered. These results suggest that measuring locomotor activity is an effective tool for identifying sleep-wake states and screening sleep-disorder drugs at low cost and with less burden to animal subjects.

Dataset Information

Efficacy and safety assessment of a TRAF6-targeted nanoimmunotherapy in atherosclerotic mice and non-human primates.

Publications

Efficacy and safety assessment of a TRAF6-targeted nanoimmunotherapy in atherosclerotic mice and non-human primates.

Similar Datasets

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