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Gene expression profiling of MT-2 cells treated with interferon-alpha and ascorbic acid (dose response)

ABSTRACT: Background: Clear guidelines for therapy of 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-a monotherapy and high-dose ascorbic acid (AA) monotherapy in open clinical trials. However, there is no clear evidence to support the value of one of these specific treatment approaches, due to the lack of in vivo and in vitro studies exploring and comparing the effects of high-dose AA and IFN-a treatment in the context of HAM/TSP. Principal Findings: Based on flow cytometry and thymidine incorporation, we demonstrated for the first time that high-dose AA displays superior antiproliferative and immunomodulatory effects over IFN-a in HAM/TSP PBMCs ex vivo. In addition, high-dose AA induces cell death in HTLV-1-infected T-cell lines in vitro. Microarray combined with Ingenuity Pathway Analysis revealed AA-induced modulation of genes associated with cell death and cell cycle. Conclusions: In comparison with IFN-a, high-dose AA is preferred as anti-HTLV-1 treatment in vitro, due to its superior cell death-inducing, antiproliferative and immunomodulatory effects. Considering the lack of treatment options, the mild in vivo side effects and the low cost price, high-dose AA should be further explored for its therapeutic potential in HAM/TSP treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE34572 | GEO | 2012/06/14

SECONDARY ACCESSION(S): PRJNA151017

REPOSITORIES: GEO

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Project description:Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an inflammatory neurodegenerative disease that affects motor, urinary, intestinal, and sensory functions. Typically, HAM/TSP is slowly progressive, but it may vary from limited motor disability after decades (very slow progression) to loss of motor function in a few years from disease onset (rapid). In this study, we aimed to identify prognostic biomarkers for HAM/TSP to support patient management. Thus, proteomic analysis of the cerebrospinal fluid (CSF) was performed with samples from HTLV-1 asymptomatic carriers (AC) (n=13) and HAM/TSP patients (n=21) with rapid, typical, and very slow progression using quantitative label-free liquid chromatography/tandem mass spectrometry. Enrichment analyses were also carried out to identify key biological processes associated with distinct neurological conditions in HTLV-1 infection. Candidate biomarkers were validated by ELISA in paired CSF and serum samples, and samples from HTLV-1-seronegative individuals (n=9) were used as controls. CSF analysis identified 602 proteins. Leukocyte/cell activation, immune response processes and neurodegeneration pathways were enriched in rapid progressors. Conversely, HTLV-1 AC and HAM/TSP patients with typical and very slow progression had enriched processes for nervous system development. Differential expression analysis showed that soluble vascular cell adhesion molecule 1 (sVCAM-1), chitotriosidase 1 (CHIT1), and cathepsin C (CTSC) were upregulated in HAM/TSP. However, only CHIT1 was significantly elevated after validation, particularly in HAM/TSP rapid progressors. In contrast, none of these biomarkers were altered in serum. Additionally, CSF CHIT1 levels in HAM/TSP patients positively correlated with the speed of HAM/TSP progression, defined as points in the IPEC-2 HAM/TSP disability scale per year of disease, and with CSF levels of phosphorylated neurofilament heavy chain, neopterin, CXCL5, CXCL10, and CXCL11. In conclusion, higher CSF levels of CHIT1 were associated with HAM/TSP rapid progression and correlated with other biomarkers of neuroinflammation and neurodegeneration. Therefore, we propose CHIT1 as a surrogate CSF biomarker to identify HAM/TSP patients with a worse prognosis.

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Gene expression profiling of MT-2 cells treated with interferon-alpha and ascorbic acid (dose response)

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