Minocycline modulates antigen-specific CTL activity through inactivation of mononuclear phagocytes in patients with HTLV-I associated neurologic disease
1 Viral Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892 USA
2 Department of Neurology and Geriatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544 Japan
3 Department of Immunology, Graduate School and Faculty of Medicine, University of the Ryukyus, Okinawa 903-0215 Japan
4 Department of Neurology, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298 USA
Retrovirology 2012, 9:16 doi:10.1186/1742-4690-9-16Published: 15 February 2012
The activation of mononuclear phagocytes (MPs), including monocytes, macrophages and dendritic cells, contributes to central nervous system inflammation in various neurological diseases. In HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), MPs are reservoirs of HTLV-I, and induce proinflammatory cytokines and excess T cell responses. The virus-infected or activated MPs may play a role in immuneregulation and disease progression in patients with HTLV-I-associated neurological diseases.
Phenotypic analysis of CD14+ monocytes in HAM/TSP patients demonstrated high expression of CX3CR1 and HLA-DR in CD14lowCD16+ monocytes, compared to healthy normal donors (NDs) and asymptomatic carriers (ACs), and the production of TNF-α and IL-1β in cultured CD14+ cells of HAM/TSP patients. CD14+ cells of HAM/TSP patients also showed acceleration of HTLV-I Tax expression in CD4+ T cells. Minocycline, an inhibitor of activated MPs, decreased TNF-α expression in CD14+ cells and IL-1β release in PBMCs of HAM/TSP patients. Minocycline significantly inhibited spontaneous lymphoproliferation and degranulation/IFN-γ expression in CD8+ T cells of HAM/TSP patients. Treatment of minocycline also inhibited IFN-γ expression in CD8+ T cells of HAM/TSP patients after Tax11-19 stimulation and downregulated MHC class I expression in CD14+ cells.
These results demonstrate that minocycline directly inhibits the activated MPs and that the downregulation of MP function can modulate CD8+ T cells function in HAM/TSP patients. It is suggested that activated MPs may be a therapeutic target for clinical intervention in HAM/TSP.