Oscillatory mTOR inhibition and Treg increase in kidney transplantation

Area of Science:

• Immunology
• Transplantation immunology
• Molecular medicine

Background:

• Mammalian target of rapamycin (mTOR) pathways are crucial for immune tolerance.
• Kidney transplant recipients often require immunosuppression to prevent rejection.

Purpose of the Study:

• To investigate the long-term immune-modulating effects of converting from calcineurin inhibitors (CNI) to everolimus (an mTOR inhibitor) in kidney transplant recipients over a 1-year follow-up.
• To understand the impact on immune cell populations and function.

Main Methods:

• Longitudinal study of kidney transplant recipients converting from CNI to everolimus.
• Analysis of immune cell populations (neutrophils, CD8+ T cells, CD4+ T cells, regulatory T cells [Tregs]).
• Measurement of cytokine production (interferon-gamma [IFN-γ], interleukin-17 [IL-17]).
• Assessment of S6 kinase phosphorylation (an mTOR target) in T cells in relation to everolimus serum concentrations and T cell receptor (TCR) triggering.

Main Results:

• Conversion to everolimus led to decreased neutrophils and CD8+ T cells.
• Reduced production of IFN-γ by CD8+ T cells and IL-17 by CD4+ T lymphocytes was observed.
• An increase in CD4+ CD25+ forkhead box protein 3 (FoxP3)+ regulatory T cells (Tregs) was noted, with higher proliferation rates compared to effector T cells.
• Basal S6 kinase phosphorylation was maintained, and its levels correlated with everolimus concentrations and TCR activation.

Conclusions:

• Long-term conversion to everolimus in kidney transplant recipients induces significant immune modulation.
• The observed changes in immune cell profiles and function suggest a complex mTOR-dependent immune-metabolic network.
• These findings may inform novel therapeutic strategies for kidney transplantation.