PT - JOURNAL ARTICLE AU - Anand Shah AU - Shichina Kannambath AU - Suzanne Herbst AU - Anna Reed AU - Martin Carby AU - Darius Amstrong-James TI - Late-breaking abstract: Effect of calcineurin inhibitors on the host innate immune response to invasive aspergillosis in alveolar macrophages DP - 2014 Sep 01 TA - European Respiratory Journal PG - 1423 VI - 44 IP - Suppl 58 4099 - http://erj.ersjournals.com/content/44/Suppl_58/1423.short 4100 - http://erj.ersjournals.com/content/44/Suppl_58/1423.full SO - Eur Respir J2014 Sep 01; 44 AB - IntroductionInvasive fungal infections are a major cause of mortality in solid-organ transplantation where steroids and calcineurin inhibitors (e.g. FK506) form the mainstay of immunosuppression. We previously published a novel BALB/c murine model of invasive aspergillosis with FK506 and hydrocortisone (HC) showing increased mortality from pulmonary aspergillosis compared to HC only immunosuppression.Objectives We analyse the effect of calcineurin inhibition on the innate immune response in human alveolar macrophages (AMs) and monocyte derived macrophages (MDMs) to Aspergillus fumigatusMethodsWe isolated AMs from lung transplant patients and MDMs from healthy donors and stimulated them in-vitro with A. fumigatus. Cytokine and ROS production was measured, phagocytosis quantified through FACS and Imagestream, fungal killing by 18S RNA PCR and NFAT translocation quantified through confocal microscopy.ResultsFK506 inhibits NFAT activation following A. fumigatus infection in AMs and MDMs. TNF-รก production was significantly impaired in infected human AMs in the presence of FK506 with impaired fungal killing and delayed phagocytosis. ROS production was impaired in FK506 treated MDMs suggesting a calcineurin-dependent mechanism of killing.ConclusionsOur work suggests a calcineurin-dependant innate defect in fungal killing as a cause for the increased incidence of invasive fungal infections within solid organ transplantation with an impaired innate immune response and fungal killing within lung transplant AMs. We present a MDM model of infection to obtain better mechanistic insights into the effect of calcineurin inhibitors on the innate immune response.