Ascorbic Acid Has Superior Ex Vivo Antiproliferative, Cell Death-Inducing and Immunomodulatory Effects over IFN-alpha in HTLV-1-Associated Myelopathy

作者：Moens Britta^*; Decanine Daniele; Menezes Soraya Maria; Khouri Ricardo; Silva Santos Gilvaneia; Lopez Giovanni; Alvarez Carolina; Talledo Michael; Gotuzzo Eduardo; Kruschewsky Ramon de Almeida; Galvao Castro Bernardo; Vandamme Anne Mieke; Van Weyenbergh Johan

来源：PLoS Neglected Tropical Diseases, 2012, 6(7): e1729.

DOI：10.1371/journal.pntd.0001729

Background: Clear therapeutic guidelines for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) are missing due to the lack of randomized double-blind controlled clinical trials. Moderate yet similar clinical benefit has been demonstrated for IFN-alpha and high-dose ascorbic acid (AA) monotherapy in a large open clinical trial. However, there is a lack of in vivo and in vitro studies exploring and comparing the effects of high-dose AA and IFN-alpha treatment in the context of HAM/TSP. Therefore, we performed the first comparative analysis of the ex vivo and in vitro molecular and cellular mechanisms of action of IFN-alpha and high-dose AA in HAM/TSP.
Principal Findings: Through thymidine incorporation and quantification of Th1/Th2/Th17 cytokines, we demonstrate that high-dose AA displays differential and superior antiproliferative and immunomodulatory effects over IFN-alpha in HAM/TSP PBMCs ex vivo. In addition, high-dose AA, but not IFN-alpha, induced cell death in both HAM/TSP PBMCs and HTLV-1-infected T-cell lines MT-2 and MT-4. Microarray data combined with pathway analysis of MT-2 cells revealed AA-induced regulation of genes associated with cell death, including miR-155. Since miR-155 has recently been demonstrated to up-regulate IFN-gamma, this microRNA might represent a novel therapeutic target in HAM/TSP, as recently demonstrated in multiple sclerosis, another neuroinflammatory disease. On the other hand, IFN-alpha selectively up-regulated antiviral and immune-related genes.
Conclusions: In comparison to IFN-alpha, high-dose AA treatment has superior ex vivo and in vitro cell death-inducing, antiproliferative and immunomodulatory anti-HTLV-1 effects. Differential pathway activation by both drugs opens up avenues for targeted treatment in specific patient subsets.

• 出版日期2012-7
• 单位河北医科大学