Increased expression of OX40 is associated with progressive disease in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis

Mineki Saito,Shiho Arishima,Yusuke Ohya,Hiroshi Takashima,Yuetsu Tanaka,Shuji Izumo,Fujio Umehara,Reiko Tanaka,Toshio Matsuzaki,Takashi Tokashiki,Satoshi Ishihara

doi:10.1186/1742-4690-10-51

Abstract

BackgroundOX40 is a member of the tumor necrosis factor receptor family that is expressed primarily on activated CD4+ T cells and promotes the development of effector and memory T cells. Although OX40 has been reported to be a target gene of human T-cell leukemia virus type-1 (HTLV-1) viral transactivator Tax and is overexpressed in vivo in adult T-cell leukemia (ATL) cells, an association between OX40 and HTLV-1-associated inflammatory disorders, such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), has not yet been established. Moreover, because abrogation of OX40 signals ameliorates chronic inflammation in animal models of autoimmune disease, novel monoclonal antibodies against OX40 may offer a potential treatment for HTLV-1-associated diseases such as ATL and HAM/TSP.ResultsIn this study, we showed that OX40 was specifically expressed in CD4+ T cells naturally infected with HTLV-1 that have the potential to produce pro-inflammatory cytokines along with Tax expression. We also showed that OX40 was overexpressed in spinal cord infiltrating mononuclear cells in a clinically progressive HAM/TSP patient with a short duration of illness. The levels of the soluble form of OX40 (sOX40) in the cerebrospinal fluid (CSF) from chronic progressive HAM/TSP patients or from patients with other inflammatory neurological diseases (OINDs) were not different. In contrast, sOX40 levels in the CSF of rapidly progressing HAM/TSP patients were higher than those in the CSF from patients with OINDs, and these patients showed higher sOX40 levels in the CSF than in the plasma. When our newly produced monoclonal antibody against OX40 was added to peripheral blood mononuclear cells in culture, HTLV-1-infected T cells were specifically removed by a mechanism that depends on antibody-dependent cellular cytotoxicity.ConclusionsOur study identified OX40 as a key molecule and biomarker for rapid progression of HAM/TSP. Furthermore, blocking OX40 may have potential in therapeutic intervention for HAM/TSP.

Highlights

OX40 is a member of the tumor necrosis factor receptor family that is expressed primarily on activated CD4+ T cells and promotes the development of effector and memory T cells
Consistent with previous studies, these findings suggested that OX40 expression is Tax dependent
Anti-OX40 monoclonal antibody eliminated naturally infected CD4+ T cells via antibody-dependent cell-mediated cytotoxicity (ADCC) in cultured peripheral blood mononuclear cells (PBMCs) We investigated the role of OX40 in human T-cell leukemia virus type-1 (HTLV-1) naturally infected CD4+ T cells, by testing the effects of an antihuman OX40 mAb on Tax expression

Summary

Introduction

OX40 is a member of the tumor necrosis factor receptor family that is expressed primarily on activated CD4+ T cells and promotes the development of effector and memory T cells. We showed that OX40 was overexpressed in spinal cord infiltrating mononuclear cells in a clinically progressive HAM/TSP patient with a short duration of illness. Increased concentrations of inflammatory markers such as neopterin [10], tumor necrosis factor (TNF)-α, interleukin (IL)-6, and interferon (IFN)-γ [11], and increase in HTLV1 antigen-specific intrathecal antibody synthesis [12] have been observed in the cerebrospinal fluid (CSF) of HAM/ TSP patients. It has been reported that IFN-stimulated genes were overexpressed in circulating leukocytes and the expression correlated with the clinical severity of HAM/TSP [13]. These findings indicate that a pro-inflammatory environment, associated with increased numbers of HTLV-1-infected cells, is a characteristic immunologic profile of HAM/TSP

Methods

Results

Conclusion