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

p. 1-15 Submitted by Edileide Reis (leyde-landy@hotmail.com) on 2014-08-19T14:50:24Z No. of bitstreams: 1 Ricardo Khouri.pdf: 730046 bytes, checksum: 97e66f8a63252afb3abb035fbba7cc97 (MD5) Approved for entry into archive by Delba Rosa (delba@ufba.br) on 2014-08-22T14:38:43Z (GMT) No. of bitstreams: 1 Ricardo Khouri.pdf: 730046 bytes, checksum: 97e66f8a63252afb3abb035fbba7cc97 (MD5) Made available in DSpace on 2014-08-22T14:38:43Z (GMT). No. of bitstreams: 1 Ricardo Khouri.pdf: 730046 bytes, checksum: 97e66f8a63252afb3abb035fbba7cc97 (MD5) Previous issue date: 2012-07 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-α 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-α 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-α 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-α in HAM/TSP PBMCs ex vivo. In addition, high-dose AA, but not IFN-α, 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-γ, 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-α selectively up-regulated antiviral and immune-related genes. Conclusions In comparison to IFN-α, 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.