Abstract
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.
Original language | English |
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Pages (from-to) | 230-240 |
Number of pages | 11 |
Journal | Clinical and Experimental Immunology |
Volume | 182 |
Issue number | 2 |
DOIs | |
Publication status | Published - Nov 1 2015 |
Keywords
- Everolimus
- Immunosuppression
- Kidney transplants
- mTOR
ASJC Scopus subject areas
- Immunology
- Immunology and Allergy