科研之友
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摘要
Objectives: Infusions of aminobisphonates (ABP) activate V gamma 9 delta 2T cells in vivo and induce an acute inflammatory response in 30% of patients treated for osteoporosis. Following the observation of digital thrombosis in a systemic sclerosis (SSc) patient after treatment with an intravenous ABP zoledronate (Zol), we evaluated whether patient and control peripheral blood (PB) mononuclear cell (MC, PBMC) acquire a prothrombotic phenotype in response to Zol. Results: V gamma 9 delta 2T cells of both patients and healthy donors (HD) upregulated the CD69 activation antigen and secreted tumor necrosis factor (INF)alpha in response to Zol in vitro. In addition, exposure to either Zol or lipopolysaccharide (LPS), or to both additively, induced expression of the highly procoagulant, tissue factor (TF)-1 on CD 14+ monocytes. Importantly, only Zol-induced TF-1 was blocked by a monoclonal antibody to TNF alpha. Interestingly, we found that SSc, but not HD, V delta 1+T cells were concurrently activated by Zol to produce interleukin (IL)-4. Addition of plasma from the blood of the SSc patient who developed critical digital ischemia after infusion of Zol, but neither plasma from a second patient with no adverse clinical response to Zol infusion nor of a HD, strongly enhanced Zol-induced monocyte TF-1, which could still be blocked by anti-INF alpha. Conclusion: Aminobisphonates induced secretion of TNF alpha by V gamma 9 delta 2+T cells may lead to INF alpha-dependent induction of procoagulant IF-1 induction on monocytes. In certain clinical settings, e.g., SSc, TF-1+ monocytes could play a role in triggering clinically relevant thrombosis.
- 出版日期2014-9-8
