Abstract
BackgroundImmune thrombocytopenia (ITP) is an autoimmune disease characterized as a low platelet count resulting from immune-mediated platelet destruction. Dimethyl fumarate (DMF) is widely applied for the treatment of several autoimmune diseases with immunosuppressive effect. However, whether it ameliorates ITP is unclear. This study aims to evaluate whether DMF has a preventive effect on ITP in mice.MethodsDMF (30, 60 or 90 mg/kg body weight) was intraperitoneally injected into mice followed by injection of rat anti-mouse integrin GPIIb/CD41antibody to induce ITP. Peripheral blood was isolated to measure platelet count and spleen mononuclear cells were extracted to measure Th1 and Treg cells along with detecting the levels of IFN-γ, and TGFβ-1 in plasma and CD68 expression in spleen by immuohistochemical staining. Additionally, macrophage cell line RAW264.7 was cultured and treated with DMF followed by analysis of cell apoptosis and cycle, and the expression of FcγRI, FcγRIIb and FcγRIV mRNA.ResultsDMF significantly inhibited antiplatelet antibody-induced platelet destruction, decreased Th1 cells and the expression of T-bet and IFN-γ, upregulated Treg cells and the expression of Foxp3 and TGF-β1 as well as reduced CD68 expression in the spleen of ITP mouse. DMF-treated RAW264.7 cells showed S-phase arrest, increased apoptosis and downregulated expression of FcγRI and FcγRIV. Meanwhile, in vitro treatment of DMF also decreased the expression of cyclin D1 and E2, reduced Bcl-2 level and increased Bax expression and caspase-3 activation.ConclusionsIn conclusion, DMF prevents antibody-mediated platelet destruction in ITP mice possibly through promoting apoptosis, indicating that it might be used as a new approach for the treatment of ITP.
Highlights
Immune thrombocytopenia (ITP) is an autoimmune disease characterized as a low platelet count resulting from immune-mediated platelet destruction
Dimethyl fumarate (DMF) prevents antibody-induced platelet destruction in ITP mouse model In order to assess whether DMF has a preventive effect on ITP, mice were treated with different doses of DMF (30, 60, 90 mg/kg) or vehicle for 30 min followed by intraperitoneal injection of anti-platelet antibody to trigger platelet destruction
To evaluate whether DMF exerts a role in platelet destruction in ITP mouse, DMF was administrated after injection of anti-platelet antibody and we found that DMF could still prevent platelet destruction as demonstrated by significantly higher platelet count than vehicle-treated mice (Supplementary Fig. S1)
Summary
Immune thrombocytopenia (ITP) is an autoimmune disease characterized as a low platelet count resulting from immune-mediated platelet destruction. Dimethyl fumarate (DMF) is widely applied for the treatment of several autoimmune diseases with immunosuppressive effect. On the other hand, existing studies have shown that in addition to platelet autoantibodies, cellular immune dysfunction has been reported to play a key role in the development and pathogenesis of ITP, including T cells, B cells and antigen-presenting cells [3, 5]. Different to the role of Th cells (Th1/2/19/17) in the positive regulation of immune response in ITP, regulatory T (Treg) cells plays a key role in limiting immunity and securing immune tolerance in the development of ITP as demonstrated by a significantly reduced numbers and function of Treg cells in ITP patients [9,10,11,12]
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