mTOR inhibition counterbalances the inflammatory status of immune cells in Chronic Granulomatous Disease

Publication date: Available online 1 October 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Aurélie Gabrion, Isabelle Hmitou, Despina Moshous, Bénédicte Neven, Alain Lefèvre-Utile, Jean-Sébastien Diana, Félipe Suarez, Capucine Picard, Stéphane Blanche, Alain Fischer, Marina Cavazzana, Fabien Touzot
BackgroundChronic granulomatous disease (CGD) is primary immunodeficiency caused by defective production of reactive oxygen species in phagocytic cells that results in life-threatening infections and severe inflammatory manifestations. The treatment of inflammatory manifestations remains challenging, as it can be associated with an increased risk of infections. Previous studies have shown that CGD phagocytes display a defect in autophagy and a reactive oxygen species-independent activation of the inflammasome.ObjectiveSince the intersections between autophagy and inflammasome have been observed in various diseases and microbial infections, we investigated the possible benefit of restoring the autophagy defect through rapamycin – a potent autophagy inducer -in the setting of CGD.MethodsWe studied fifteen patients diagnosed with CGD and followed in our institution. All patients were free of any active infection at the time of the study.ResultsWe show that CGD patients present a consistent inflammatory phenotype defined by (i) increased 'non-classical' and 'intermediate' monocytes (ii) a pro-inflammatory state of mononuclear phagocytes with increased IL-1β and TNF-α content (iii) a TH17 bias of CD4+ T-cells (iv) and an increase in IL-17A secreting neutrophils. We document the reversion of CGD inflammatory status by the mTOR inhibitor rapamycin on the different immune cell subsets. We also provide evidence for the enhancement of rapamycin inhibitory effect on IL-1β secretion by the IL-1 receptor antagonist anakinra in CGD phagocytes.ConclusionAltogether these data open new therapeutic approaches for CGD inflammatory manifestations.

Teaser

This study provides evidence that rapamycin - a potent mTOR inhibitor and autophagy inducer - counterbalances the inflammatory status of immune cells in patients with chronic granulomatous disease, opening the field for its use for the treatment of CGD inflammatory manifestations.


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