1. mTOR Inhibition Impairs the Activation and Function of Belatacept-Resistant CD4 + CD57 + T Cells In Vivo and In Vitro.
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Herr, Florence, Dekeyser, Manon, Le Pavec, Jerome, Desterke, Christophe, Chiron, Andrada-Silvana, Bargiel, Karen, Mercier, Olaf, Vernochet, Amelia, Fadel, Elie, and Durrbach, Antoine
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GRAFT rejection ,T cells ,CD4 antigen ,GRAFT survival ,BELATACEPT ,MTOR inhibitors - Abstract
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. [ABSTRACT FROM AUTHOR]- Published
- 2023
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