Human T-cell leukemia virus type 1 (HTLV-1) was the first human oncogenic retrovirus to be identified and associated with distinct human diseases, such as adult T-cell leukemia (ATL) [
1,
2] and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) [
3,
4]. HAM/TSP is a chronic inflammatory disease of the central nervous system (CNS), pathologically characterized by perivascular lymphocytic cuffing and parenchymal lymphocytic infiltration, including HTLV-1-infected CD4
+ T-cells [
5]. This pathological condition causes severe dysfunction of the corticospinal (pyramidal) tracts of the spinal cord, resulting in urinary failures and leg paralysis, which are the main clinical symptoms of HAM/TSP [
6]. In addition to these neurological symptoms, some patients with HAM/TSP also exhibit autoimmune-like inflammatory disorders such as uveitis, arthritis, T-lymphocyte alveolitis, polymyositis, and Sjögren’s syndrome [
7]. Like many autoimmune diseases, pro-inflammatory cytokines, chemokines, and matrix metalloproteinases act as important effectors of tissue damage in patients with HAM/TSP [
8]. Particularly, the overexpression of interferon (IFN)-stimulated genes in circulating leukocytes has been observed, and the expression correlated with the clinical severity of HAM/TSP [
9]. Furthermore, increased concentrations of inflammatory markers, such as neopterin [
10], tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IFN-γ [
11], and an increase in HTLV-1 antigen-specific intrathecal antibody synthesis [
12] have been observed in the cerebrospinal fluid (CSF) of patients with HAM/TSP. These findings indicate that a pro-inflammatory environment, associated with increased numbers of HTLV-1-infected and activated T-cells, is a characteristic immunologic profile of HAM/TSP. Accordingly, anti-inflammatory drugs, such as prednisolone [
13] and IFN-α [
14], have been approved for the treatment of HAM/TSP. However, such drugs often have insufficient effects, various side effects, and are expensive for long-term treatment. Therefore, it is important to develop strategies that are effective and tolerable, even for long-term or lifelong treatment.
Chemokine (C-C motif) ligand 1 (CCL1) is a small glycoprotein secreted by monocytes, activated macrophages, and T-lymphocytes that belongs to a family of inflammatory cytokines known as chemokines [
15,
16]. It has been reported that CCL1 is overexpressed in ATL cells, mediating an autocrine anti-apoptotic loop, along with its receptor, CC chemokine receptor 8 (CCR8), for in vivo growth and survival of leukemic cells [
17]. Because CCL1 is known to induce cytokine secretion and direct the trafficking of immune cells, increased CCL1 expression might be associated with leukocyte mobilization in vivo, and thus also contributing to chronic inflammatory conditions. If this is the case, interfering with CCL1 function may be a promising approach for novel anti-inflammatory treatment against HAM/TSP.
In this study, we investigated the possible role of CCL1 in patients with HAM/TSP, and suggest minocycline as a novel immunomodulatory drug against HAM/TSP, partly due to its inhibitory effect on CCL1 expression.