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IMEN BOUABANE, CLAUDE ALAIN MAURAGE, JACQUES TRAUET, MYRIAM LABALETTE, JEAN-PAUL DESSAINT, PIERRE LABALETTE; Ocular Granulomatosis Associated With Brimonidine Treatment. Does Brimonidine Have An Effect On Human Macrophages And Dendritic Cells In Vitro?. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4010.
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Conjunctival and episcleral granulomas with uveitis have been reported as a side effect of antiglaucomatous topical use of brimonidine tartrate. We postulated that brimonidine is implicated in this inflammatory process and studied its effects on the antigen presenting cells (APCs) cytokines production.
Conjunctival and episcleral granulomatous lesions were immunohistochemically analyzed for CD3, CD4, CD8, CD1a, CD11c, CD68, and CD123.Macrophages, immatures and matures dendritic cells (DCs) were generated from peripheral blood monocytes of healthy donors and of patients who presented uveitis and granulomatous ocular infiltration induced by brimonidine topical treatment. Macrophages obtained from a human leukemia cell-line THP-1 were also studied. APCs were respectively exposed to preserved brimonidine tartrate suspension (0.012%), unpreserved brimonidine tartrate suspension, 0.05% benzalkonium chloride (BAK) and lipopolysaccharides (LPS) during 4 hours. Cell viability was evaluated by flow cytometry with propidium iodide (PI) and dihexyloxacarbocyanine (DiOC) staining. After exposure to the different treatments, APCs Th1/Th2 cytokines production was measured in supernatants by multiplex flow cytometry and ELISA.
The granulomas consisted predominantly of CD4+ T-cells and APCs, i.e. epithelioid macrophages CD 68+ and myeloid DCs CD11c+.PI and DiOC analysis showed no cellular toxicity with used brimonidine tartrate and BAK concentrations. Comparative exposure of APCs to unpreserved or preserved brimonidine tartrate formulations, or BAK alone, induced similar amounts of pro (IL-6 or TNF-α) and anti (IL-10) inflammatory cytokines. On the other hand, brimonidine tartrate and BAK reduced the LPS-stimulated production of IL-6, TNF-α and IL-10. Inhibition of IL-10 production was predominantly observed with immatures DCs generated from patients.
Dendritic cells IL-10 production was associated with an immune tolerance. By altering the APCs IL-10 production, brimonidine tartrate will affect induction of tolerance by DCs and allow initiation of immune response leading to granulomas formation.
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