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• W233497114 abstract "Background: Clinical studies indicate that treatment with CCR5 antagonist maraviroc (MVC) induces a greater immunologic benefit beyond that attributable to its antiviral activity. The mechanisms underlying this phenomenon are unknown and data on the in vitro direct effect of the drug on immune system are lacking. Objective: to study the in vitro direct effect of MVC on several immune cells, as PBMC, neutrophils (PMN), mature and immature dendritic cells (DCs) and macrophages (MO), by assessing apoptosis, cell viability and cell migration. Methods: PBMC and PMN were isolated from healthy donors buffy coat. MO and DCs were generated from adherent monocytes cultured for 6 days in the presence of GM-CSF (50 ng/ml) alone or GM-CSF with IL-4 (40 ng/ml), respectively. To induce maturation, cells were cultured with medium containing LPS (0.1 mg/ml) for additional 24 hrs. The cells (2 X 10 6 /ml) were pre-incubated with different concentrations of MVC. Apoptosis of both PBMC and PMNL was assessed by the activity of caspase 3 in cell lysates. The chemotactic activity of PMN, DC and MO was assessed using FMLP (10-6M) as chemoattractant and measured by both microscopy and cytometry. Results: No significant variations on apoptosis was detectable after 24hrs incubation with all MVC concentrations used for both PBMC (CNT: 0.21+0.001; MVC 200nM: 0.20+0.01; MVC 20μM 0.19+0.01), and PMNL (CNT: 0.18+0.09; MVC 200nM: 0.13+0.02; MVC 20μM 0.159+0.05). In vitro treatment with MVC induced a 70% and 80% reduction of chemotactic activity in both PMN and PBMC. In addition, MVC used at therapeutic concentration (0.1 mM) reduced chemotaxis only in mature MO and DC (mean+SD: 12+0,2 of migrated cells versus 36 +7 for MO and 36+1,4 of migrated cells versus 78+10 for MDC; p<0.05). When immature cells were assessed, MVC did not affect chemotactic activity of both MO and DC within the range of therapeutically achievable concentrations in the patients. Immature MO and DC chemotaxis was inhibited only at higher concentration tested (10 mM). Conclusions: These data indicate that CCR5 antagonist MVC has a direct effect on innate immune cells by mechanism which could be independent from anti-HIV activity. We demonstrated that in vitro treatment with MVC significantly inhibits chemotactic activity of PMN, MO and DC. These findings suggest that MVC might have a potential role in the downregulation of HIV-associated chronic inflammation by blocking the recirculation and trafficking of MO and DC. Our results showed that MVC did not alter the apoptosis of PBMC and PMNL, and no significant effect of MVC was seen for PBMC in the modulation of apoptosis exogenously induced with the stressing agents puromicyn. (Fig 1-2)" @default.
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• W233497114 date "2009-01-01" @default.
• W233497114 modified "2023-09-26" @default.
• W233497114 title "In vitro Effect of CCR5 Antagonists on Innate Immune System: Maraviroc Inhibits the Migration of Neutrophils, Macrophages and Dendritic Cells" @default.
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