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Updated: Jun 18, 2026
Determining Immune System Suppression versus CNS Protection for Pharmacological Interventions in Autoimmune Demyelination
Published on: September 12, 2016
Catastrophic NAD+ depletion in activated T lymphocytes through Nampt inhibition reduces demyelination and disability
Santina Bruzzone1, Floriana Fruscione, Sara Morando
1Department of Experimental Medicine, Section of Biochemistry, University of Genoa, Genoa, Italy.
Abstract:
Nicotinamide phosphoribosyltransferase (Nampt) inhibitors such as FK866 are potent inhibitors of NAD(+) synthesis that show promise for the treatment of different forms of cancer. Based on Nampt upregulation in activated T lymphocytes and on preliminary reports of lymphopenia in FK866 treated patients, we have investigated FK866 for its capacity to interfere with T lymphocyte function and survival. Intracellular pyridine nucleotides, ATP, mitochondrial function, viability, proliferation, activation markers and cytokine secretion were assessed in resting and in activated human T lymphocytes. In addition, we used experimental autoimmune encephalomyelitis (EAE) as a model of T-cell mediated autoimmune disease to assess FK866 efficacy in vivo. We show that activated, but not resting, T lymphocytes undergo massive NAD(+) depletion upon FK866-mediated Nampt inhibition. As a consequence, impaired proliferation, reduced IFN-gamma and TNF-alpha production, and finally autophagic cell demise result. We demonstrate that upregulation of the NAD(+)-degrading enzyme poly-(ADP-ribose)-polymerase (PARP) by activated T cells enhances their susceptibility to NAD(+) depletion. In addition, we relate defective IFN-gamma and TNF-alpha production in response to FK866 to impaired Sirt6 activity. Finally, we show that FK866 strikingly reduces the neurological damage and the clinical manifestations of EAE. In conclusion, Nampt inhibitors (and possibly Sirt6 inhibitors) could be used to modulate T cell-mediated immune responses and thereby be beneficial in immune-mediated disorders.
Insights
Nicotinamide phosphoribosyltransferase (Nampt) inhibitors like FK866 deplete NAD(+) in activated T cells, impairing their function and survival. This suggests potential for treating T-cell mediated autoimmune diseases.
Area of Science:
- Immunology
- Biochemistry
- Pharmacology
Background:
- Nicotinamide phosphoribosyltransferase (Nampt) inhibitors, such as FK866, target NAD(+) synthesis and show anti-cancer potential.
- Nampt is upregulated in activated T lymphocytes, and FK866 treatment has been linked to lymphopenia, suggesting an impact on T cell function.
Purpose of the Study:
- To investigate the effects of FK866 on human T lymphocyte function and survival.
- To evaluate the efficacy of FK866 in a T-cell mediated autoimmune disease model (EAE).
Main Methods:
- Assessed intracellular pyridine nucleotides, ATP, mitochondrial function, viability, proliferation, activation markers, and cytokine secretion in resting and activated human T lymphocytes.
- Utilized experimental autoimmune encephalomyelitis (EAE) as an in vivo model for T-cell mediated autoimmune disease.
Main Results:
- Activated T lymphocytes, but not resting ones, showed significant NAD(+) depletion with FK866 treatment.
- FK866 induced impaired T cell proliferation, reduced IFN-gamma and TNF-alpha production, and autophagic cell death.
- FK866 treatment markedly reduced neurological damage and clinical symptoms in the EAE model.
Conclusions:
- Nampt inhibition by FK866 selectively affects activated T lymphocytes, leading to impaired function and cell death.
- FK866 demonstrates therapeutic potential in modulating T-cell mediated immune responses, suggesting its utility in autoimmune disorders.
