mTOR Inhibition Impairs the Activation and Function of Belatacept-Resistant CD4+CD57+ T Cells In Vivo and In Vitro - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Pharmaceutics Année : 2023

mTOR Inhibition Impairs the Activation and Function of Belatacept-Resistant CD4+CD57+ T Cells In Vivo and In Vitro

Résumé

Calcineurin inhibitors have improved graft survival in solid-organ transplantation but their use is limited by toxicity, requiring a switch to another immunosuppressor in some cases. Belatacept is one option that has been shown to improve graft and patient survival despite being associated with a higher risk of acute cellular rejection. This risk of acute cellular rejection is correlated with the presence of belatacept-resistant T cells. We performed a transcriptomic analysis of in vitro-activated cells to identify pathways affected by belatacept in belatacept-sensitive cells (CD4+CD57−) but not in belatacept-resistant CD4+CD57+ T cells. mTOR was significantly downregulated in belatacept-sensitive but not belatacept-resistant T cells. The inhibition of mTOR strongly decreases the activation and cytotoxicity of CD4+CD57+ cells. In humans, the use of a combination of mTOR inhibitor and belatacept prevents graft rejection and decreases the expression of activation markers on CD4 and CD8 T cells. mTOR inhibition decreases the functioning of belatacept-resistant CD4+CD57+ T cells in vitro and in vivo. It could potentially be used in association with belatacept to prevent acute cellular rejection in cases of calcineurin intolerance.

Dates et versions

hal-04520002 , version 1 (25-03-2024)

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Citer

Florence Herr, Manon Dekeyser, Jerome Le Pavec, Christophe Desterke, Andrada-Silvana Chiron, et al.. mTOR Inhibition Impairs the Activation and Function of Belatacept-Resistant CD4+CD57+ T Cells In Vivo and In Vitro. Pharmaceutics, 2023, 15 (4), pp.1299. ⟨10.3390/pharmaceutics15041299⟩. ⟨hal-04520002⟩
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