Abstract
Abstract 4732Nicotinamide 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 TNF-a production, ATP shortage, and, finally, autophagic cell demise result. We demonstrate that upregulation of the of the NAD+-degrading enzyme poly-(ADP-ribose)-polymerase (PARP) by activated T cells enhances their susceptibility to NAD+ depletion. We relate defective TNF-a production in response to FK866 to impaired SIRT6 activity. Finally, in line with its capacity to interfere with T lymphocyte function and survival, we show that FK866 strikingly reduces the neurological damage and the clinical manifestations of EAE. In conclusion, Nampt inhibitors (and possibly sirtuin inhibitors) could be used to modulate T cell-mediated immune responses and thereby be beneficial in immune-mediated disorders. Disclosures:No relevant conflicts of interest to declare.
Highlights
FK866 is a potent inhibitor of nicotinamide phosphoribosyltrabsferase (Nampt), the key enzyme in the NAD+ synthesis pathway from Nam [1,2,3]
We found that FK866 was toxic to Peripheral Blood Lymphocyte (PBL) when these were concomitantly activated with mitogens [phytohematoagglutininP (PHA), or concanavalin A (Con A)], while unstimulated cells were mostly unaffected (Figure 1B)
We show that activated T lymphocytes are crucially dependent on Nampt activity for their function and survival as they face massive NAD+ depletion and cell demise when this enzyme is obstructed with FK866
Summary
FK866 (formerly WK175) is a potent inhibitor of nicotinamide phosphoribosyltrabsferase (Nampt), the key enzyme in the NAD+ synthesis pathway from Nam [1,2,3]. Initial studies carried out in cancer cell lines indicated that exposure to FK866 results in a slowly progressing form of cell death due to intracellular NAD+ depletion [1,4]. The preclinical studies and the clinical experimentation revealed that lymphocytes are probably the normal cell type that is most sensitive to FK866 since lymphopenia was consistently observed in response to this drug [5]. In line with these findings, using a mouse strain lacking Nampt expression in the T and B cell lineage, Rongavaux and colleagues have recently shown that Nampt is critically required for the development of both T and B lymphocytes [9]. T lymphocytes upregulate Nampt in response to mitogenic stimuli [10,11,12,13], suggesting that Nampt activity may be especially required during the process of T lymphocyte activation
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