Oscillatory mTOR inhibition and Treg increase in kidney transplantation. (28th August 2015)

• Record Type: Journal Article
• Authors: Sabbatini, M; Ruggiero, G; Palatucci, A T; Rubino, V; Federico, S; Giovazzino, A; Apicella, L; Santopaolo, M; Matarese, G; Galgani, M; Terrazzano, G
• Is Part Of: Clinical and experimental immunology. Volume 182:Number 2(2015:Nov.)
• Page Start: 230
• Page End: 240
• Publication Date: 2015-08-28
• Subjects: everolimus -- immunosuppression -- kidney transplants -- mTOR; Immunopathology -- Periodicals; 616.079
• DOI: 10.1111/cei.12669
• Languages: English
• ISSNs: 0009-9104

Abstract

Summary: Intracellular metabolic pathways dependent upon the mammalian target of rapamycin (mTOR) play a key role in immune-tolerance control. In this study, we focused on long-term mTOR-dependent immune-modulating effects in kidney transplant recipients undergoing conversion from calcineurin inhibitors (CNI) to mTOR inhibitors (everolimus) in a 1-year follow-up. The conversion to everolimus is associated with a decrease of neutrophils and of CD8 + T cells. In addition, we observed a reduced production of interferon (IFN)-γ by CD8 + T cells and of interleukin (IL)-17 by CD4 + T lymphocytes. An increase in CD4 + CD25 + forkhead box protein 3 (FoxP3) + [regulatory T cell [(Treg )] numbers was also seen. Treg increase correlated with a higher proliferation rate of this regulatory subpopulation when compared with the CD4 + FoxP3 − effector counterpart. Basal phosphorylation level of S6 kinase, a major mTOR-dependent molecular target, was substantially maintained in patients treated with everolimus. Moreover, oscillations in serum concentration of everolimus were associated with changes in basal and activation-dependent S6 kinase phosphorylation of CD4 + and CD8 + T cells. Indeed, T cell receptor (TCR) triggering was observed to induce significantly higher S6 kinase phosphorylation in the presence of lower everolimus serum concentrations. These results unveil the complex mTOR-dependent immune-metabolic network leading to long-term immune-modulation and might have relevance for novel therapeutic settings in kidney transplants.