Molecular and clinical effects of betamethasone in human t‐cell lymphotropic virus type‐i‐associated myelopathy/tropical spastic paraparesis patients

Abstract

There is no effective therapy for human T-cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Glucocorticoids are effective to reduce the motor disability in these patients, but its role as anti-spastic drugs is unknown. Here it is reported the use of corticosteroids in HAM/TSP. The goal was to find reliable molecular markers linked to treatment effectiveness. The clinical efficacy of corticosteroids was studied in 22 HAM/TSP. The treatment was a single dose of 7.0 mg of systemic betamethasone. Pre-treatment samples were obtained immediately before steroid administration and post-treatment samples were collected after 5 days. Neurological disability was evaluated by the Osame's Motor Disability Scales. Relative levels of Tax, Foxp3, IL-10, TGF-β, CTLA-4, and GITR mRNA were measured and the percentage of CD4(+) Foxp3(+) and CD4(+) Tax(+) populations was quantified in PBMCs by real-time PCR and flow cytometry, respectively. The same parameters were studied in eight untreated carriers. Betamethasone treatment showed neurological improvement in 21 HAM/TSP patients, with one patient without response to treatment. This therapy was associated with a decrease in Tax mRNA load and CD4(+) Tax(+) T cells in HAM/TSP. Simultaneously, an increase in Foxp3 mRNA and CD4(+) Foxp3(+) T cell was detected in these patients. The other markers studied had no significant changes after treatment. Clinical improvement in betamethasone-treated HAM/TSP was associated with an inverse relationship between a decrease in Tax and an increase in Foxp3 at the mRNA and protein levels. These results suggest that both Tax and Foxp3 may represent potential biomarkers for drug treatment assessments in HAM/TSP.

Cerebrospinal Fluid Neopterin, but not Osteopontin, is a Valuable Biomarker for the Treatment Response in Patients with HTLV-I-associated Myelopathy

“…Moreover, corticosteroids may also affect the HTLV-I infected cells or the immune response to HTLV-I. It has been demonstrated that betamethasone therapy decreased CD4 (24). Corticosteroids therapy may reduce the erratic IFN-γ production by T-cells in patients with HAM/TSP, which is then followed by a reduction of neopterin release by the stimulated macrophages.…”

Tax and Semaphorin 4D Released from Lymphocytes Infected with Human Lymphotropic Virus Type 1 and Their Effect on Neurite Growth

“…+ cytotoxic T lymphocytes, 20 nM concanamycin A was added to the culture media (Sigma-Aldrich, St Louis, MO) as performed by Alberti et al (2000). 42 The counting of viable and nonviable cells was measured by 0.4% trypan blue exclusion dye (Sigma-Aldrich). This method showed more than 95% viable PBMCs, which agrees with the manufacturer's statement (Amersham Bioesciences).…”

“…42 Cells were harvested and stained with fluorophore-conjugated antibodies from eBiosciences (San Diego, CA): CD4-PE (Catalog No. PBMCs cultured in RPMI 1640 + GlutaMAX, 10% iFBS, and 20 nM concanamycin A were treated with or without anti-Tax (Covalab, Catalog No.…”

Tax Posttranslational Modifications and Interaction with Calreticulin in MT-2 Cells and Human Peripheral Blood Mononuclear Cells of Human T Cell Lymphotropic Virus Type-I-Associated Myelopathy/Tropical Spastic Paraparesis Patients

“…After 24 h culture, PBMCs from HTLV-1-infected patients expressed Tax protein at detectable levels by flow cytometry, 7 but not by western blot. Nevertheless, secreted Tax can be followed by western blot in PBMC culture medium, which indicates Tax secretion.…”

“…3,4 Regarding infection, T-CD4 + cells are the in vivo reservoir of the virus, mainly CD4 + FoxP3 + cells or T reg . [5][6][7] Human cerebral endothelial cells have been shown to be susceptible to retroviral infection, producing a dysfunction of the blood-brain barrier by alteration in the expression of tight-junction proteins. 8 This could be an important mechanism for the infiltration of infected lymphocytes into the central nervous system (CNS) and also facilitates astrocyte infection.…”