Minocycline modulates antigen-specific CTL activity through inactivation of mononuclear phagocytes in patients with HTLV-I associated neurologic disease

BACKGROUND: 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. RESULTS: Phenotypic analysis of CD14(+ )monocytes in HAM/TSP patients demonstrated high expression of CX(3)CR1 and HLA-DR in CD14(low)CD16(+ )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. CONCLUSION: 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.