Abstract
Human T lymphotropic virus type 1 (HTLV-1) is the causal agent of myelopathy/tropical spastic paraparesis (HAM/TSP), a disease mediated by the immune response. HTLV-1 induces a spontaneous proliferation and production of pro-inflammatory cytokines by T cells, and increasing interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) levels are potentially involved in tissue damage in diseases related to HTLV-1. This exaggerated immune response is also due to an inability of the natural regulatory mechanisms to down-modulate the immune response in this group of patients. TNF-α inhibitors reduce inflammation and have been shown to improve chronic inflammatory diseases in clinical trials. The aim of this study was to evaluate the ability of pentoxifylline, forskolin, rolipram, and thalidomide to decrease in vitro production of TNF-α and IFN-γ in cells of HTLV-1-infected subjects. Participants of the study included 19 patients with HAM/TSP (mean age, 53 ± 11; male:female ratio, 1:1) and 18 HTLV-1 carriers (mean age, 47 ± 11; male:female ratio, 1:2.6). Cytokines were determined by ELISA in supernatants of mononuclear cell cultures. Pentoxifylline inhibited TNF-α and IFN-γ synthesis with the minimum dose used (50 µM). The results with forskolin were similar to those observed with pentoxifylline. The doses of rolipram used were 0.01-1 µM and the best inhibition of TNF-α production was achieved with 1 µM and for IFN-γ production it was 0.01 µM. The minimum dose of thalidomide used (1 µM) inhibited TNF-α production but thalidomide did not inhibit IFN-γ production even when the maximum dose (50 µM) was used. All drugs had an in vitro inhibitory effect on TNF-α production and, with the exception of thalidomide, all of them also decreased IFN-γ production.
Highlights
Human lymphotropic virus type 1 (HTLV-1) infection is endemic in Brazil [1] and the city of Salvador has the highest prevalence among blood donors (1.35%) and in the population (1.76%) [2,3]
Study design and patient selection This was an experimental in vitro study evaluating the effect of four tumor necrosis factor-α (TNF-α) inhibitors, i.e., pentoxifylline, forskolin, rolipram, and thalidomide, in peripheral blood mononuclear cells (PBMC) of individuals infected with Human T lymphotropic virus type 1 (HTLV-1)
These cytokines are increased in serum and cerebrospinal fluid (CSF) and stimulate nitric oxide (NO) and metalloproteinase synthesis [18]
Summary
Human lymphotropic virus type 1 (HTLV-1) infection is endemic in Brazil [1] and the city of Salvador has the highest prevalence among blood donors (1.35%) and in the population (1.76%) [2,3]. HAM/TSP is characterized by progressive spastic paraparesis and occurs in less than 5% of HTLV-1-infected patients [7]. High proviral load [8,9] and increased expression of the pro-inflammatory cytokines TNF-α and IFN-γ in PBMC as well as interleukin-1 (IL-1) and IL-6 in the cerebrospinal fluid (CSF) are associated with this disease [4,10]. These cytokines are more pronounced in HAM/TSP patients, evidence of enhanced T-cell activation is detected in HTLV-1 carriers [11]. A large proportion of HTLV-I carriers, they do not fulfill the criteria for HAM/TSP, have neurologi-
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