Abstract: TH-PO051

Azithromycin Modulates Giant Cell Formation in Granulomatosis with Polyangiitis (GPA)

Session Information

Category: Glomerular

  • 1001 Glomerular: Basic/Experimental Immunology and Inflammation

Authors

  • Henderson, Scott R, University College London, London, United Kingdom
  • Phua, Nixon, University College London, London, United Kingdom
  • Salama, Alan D., University College London, London, United Kingdom
Background

Macrolides have immunomodulatory properties influencing both innate and adaptive immune responses. Anti-inflammatory effects have been established on neutrophils, CD4 positive T cells and monocytes and macrophages. Monocytes are central to disease pathogenesis in GPA, with critical importance in the development of granulomatous inflammation which remains one of the hardest manifestations to treat. We have established a novel in vitro giant cell/granuloma model with GPA patients’ cells and established the significance of persistent PR3 exposure on giant cell and granuloma formation in GPA patients. Upper and lower airway manifestations of GPA are often treated with macrolide adjuvant therapy and we described a case of apparent recovery from more severe vasculitic features with azithromycin alone. Therefore, we set out to evaluate whether modulating monocyte responses to PR3 with azithromycin would result in reduced giant cell formation in GPA patients.

Methods

Monocytes were isolated from healthy controls, GPA and microscopic polyangiitis (MPA) patients and stimulated with either proteinase-3 (PR3) (10ug/ml) or myeloperoxidase (MPO) (10ug/ml) and varying concentrations of azithromycin (0.5, 2, 5ug/ml) for 72 hours. Semi-automated fusion index was calculated, a measure of MGC formation, using imaging software. Cytometric bead assays were used to evaluate modulation of cytokine production.

Results

Spontaneous rates of giant cell formation were greatest in GPA patients (n=4). The addition of PR3 but not MPO significantly increased giant cell formation in GPA patients compared to healthy controls (n=4) and MPA patients (n=4) (p 0.02). Addition of Azithromycin decreased giant cell formation in GPA patients (p 0.001) with the greatest effect seen at a concentration of 5ug/ml (p 0.03), but was also observed at 2ug/ml (p 0.003). IL-6 was important in the formation of giant cells. Although levels remained unchanged despite a reduction in giant cell formation at 72 hours in the presence of azithromycin and PR3, a reduction in IL-1b and an increase in IL-10 levels were observed.

Conclusion

Anti-inflammatory and anti-bacterial treatment is important in the maintenance therapy of GPA. Azithromycin may therefore offer a new alternative adjunctive treatment to this strategy whilst being a cost-effective, safe therapeutic option.