RESUMEN
BACKGROUND: CpG ODN are synthetic single stranded DNA sequences that act as immunostimulants. They have been increasingly used to treat several cancers, however, thrombocytopenia is a potential recognized side effect of some sequences. OBJECTIVES: We tested the ability of two CpG ODN (ODN 2395 and ISIS 120704) to induce thrombocytopenia when administered to BALB/c mice and determined mechanisms associated with thrombocytopenia. METHODS: BALB/c mice were pre-bled and then injected with titrated doses of CpG ODNs and platelet counts were determined. The mice were treated IVIg or with various inhibitors and antagonists of toll-like receptor 9 (TLR9) and spleen tyrosine kinase (Syk) to determine their effects on the thrombocytopenia. RESULTS AND CONCLUSIONS: Compared with saline-treated mice or mice treated with 2'-O-methoxyethyl (MOE)-modified antisense (ASO) ODN, both ODN 2395 and ISIS 120704 induced an acute dose-dependent thrombocytopenia within 3 and 24 hours respectively. The thrombocytopenia was associated with significant increases in plasma monocyte chemoattractant protein 1 (MCP1). Intravenous immunoglobulin (IVIg) administration significantly rescued the CpG ODN-induced thrombocytopenia, as did treatment with either a Syk-inhibitor or TLR9 antagonists. In vitro, CpG ODN could activate human platelets and this correlated significantly with enhanced IVIg- and Syk-dependent phagocytosis by THP-1 monocytes. These results suggest that CpG ODN induce an acute inflammatory-associated (IVIg-sensitive) thrombocytopenia that can be alleviated by Syk- or TLR9-blockade, and an IVIg- and Syk-dependent platelet clearance pathway appears primarily responsible for the thrombocytopenia. Whether these results are applicable to humans still has to be elucidated.
Asunto(s)
Plaquetas , Púrpura Trombocitopénica Idiopática , Factor de Crecimiento Transformador beta , Humanos , Púrpura Trombocitopénica Idiopática/sangre , Púrpura Trombocitopénica Idiopática/inmunología , Factor de Crecimiento Transformador beta/inmunología , Plaquetas/inmunología , Plaquetas/metabolismo , Tolerancia Inmunológica , Masculino , FemeninoRESUMEN
Immune thrombocytopenia (ITP) is an autoimmune bleeding disease caused by immune-mediated platelet destruction and decreased platelet production. ITP is characterized by an isolated thrombocytopenia (<100 × 109/L) and increased risk of bleeding. The disease has a complex pathophysiology wherein immune tolerance breakdown leads to platelet and megakaryocyte destruction. Therapeutics such as corticosteroids, intravenous immunoglobulins (IVIg), rituximab, and thrombopoietin receptor agonists (TPO-RAs) aim to increase platelet counts to prevent hemorrhage and increase quality of life. TPO-RAs act via stimulation of TPO receptors on megakaryocytes to directly stimulate platelet production. Romiplostim is a TPO-RA that has become a mainstay in the treatment of ITP. Treatment significantly increases megakaryocyte maturation and growth leading to improved platelet production and it has recently been shown to have additional immunomodulatory effects in treated patients. This review will highlight the complex pathophysiology of ITP and discuss the usage of Romiplostim in ITP and its ability to potentially immunomodulate autoimmunity.