Ascorbic acid has superior ex vivo antiproliferative,cell death-inducing and immunomodulatory effects over IFN-α in HTLV-1-associated myelopathy

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. © 2012 moens et al.