期刊
CLINICAL AND EXPERIMENTAL IMMUNOLOGY
卷 182, 期 2, 页码 230-240出版社
WILEY-BLACKWELL
DOI: 10.1111/cei.12669
关键词
everolimus; immunosuppression; kidney transplants; mTOR
类别
资金
- Basilicata Innovazione Grant
- Universita della Basilicata
- SANYpet SpA donation
- Fondazione Italiana Sclerosi Multipla (FISM) [2012/R/11]
- European Union IDEAS Programme European Research Council Starting Grant menTORingTregs [310496]
- CNR Medicina Personalizzata, FIRB-MERIT [RBNE08HWLZ_15]
- Italian Space Agency (ASI) [2014-033-R.O]
- JDRF [1-PNF-2015-115-5-B]
- R.I.L
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)-gamma 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 [(T-reg)] numbers was also seen. T-reg 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.
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