Abstract
Antiphospholipid syndrome (APS) is an autoimmune disease characterized by the production of β2-glycoprotein I (β2GPI)-dependent autoantibodies, with vascular thrombosis or obstetrical complications. Around 20% of APS patients are refractory to current treatments. Crassolide, a cembranoid diterpene extracted from soft corals, is a potential therapeutic candidate. Here, to examine the anti-inflammatory properties of crassolide, we first determined its effects on bone marrow-derived and splenic dendritic cells (DC). Specifically, we applied lipopolysaccharide (LPS) or β2GPI stimulation and measured the expressions of CD80 and CD86, and secretions of cytokines. We also determined in the OT-II mice, if bone marrow-derived DC was able to stimulate antigen-specific T cells. Moreover, we examined the therapeutic potential of crassolide postimmunization in a murine model of APS that depended on active immunization with β2GPI. The vascular manifestations were evaluated in terms of fluorescein-induced thrombi in mesenteric microvessels, whereas the obstetric manifestations were evaluated based on the proportion of fetal loss after pregnancy. We also measured blood titers of anti-β2GPI antibody, splenic cell proliferative responses and cytokine secretions after β2GPI stimulation ex vivo. Finally, we determined in these mice, hematological, hepatic and renal toxicities of crassolide. Crassolide after LPS stimulation suppressed DC maturation and secretion of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-12 and IL-23, and downstream T cell activation. Crassolide could partially ameliorate both the vascular and obstetric manifestations of APS in BALB/c mice. Both blood titers of anti-β2GPI antibody and splenic cell proliferation after β2GPI stimulation were reduced. Splenic Th1 and Th17 responses were also lowered after β2GPI stimulation. Finally, within therapeutic doses of crassolide, we found no evidence of its toxicity. In conclusion, we showed the ability of crassolide to suppress DC and downstream T cell responses. Crassolide is therefore a potential candidate for adjunctive therapy in APS.
Highlights
Antiphospholipid syndrome (APS) is an autoimmune disease characterized by the production of β2-glycoprotein I (β2GPI)-dependent antiphopholipid autoantibodies, arterial/venous thrombosis or obstetrical complications [1]
We have conducted the first study on the therapeutic potential of crassolide, a cembranoid diterpene extracted from soft corals, in a murine model of APS
Our earlier work on dendritic cells (DC) evaluated the effect of sinulariolide, another cembranoid diterpene derived from Sinularia flexibilis [30]
Summary
Antiphospholipid syndrome (APS) is an autoimmune disease characterized by the production of β2-glycoprotein I (β2GPI)-dependent antiphopholipid autoantibodies (like APL, including lupus anticoagulant, anticardiolipin antibody, anti-β2GPI antibody), arterial/venous thrombosis or obstetrical complications [1]. About 20% of patients with vascular APS develop recurrent thrombosis despite such standard therapy [7]. Current therapy fails in 20–30% of patients with obstetric APS [8]. Such treatment strategy inevitably carries the risk of hemorrhage [9], with annual major bleeding rates between 0.57 and 10% [10]. These shortcomings indicate the need for developing new adjunctive therapeutic interventions for this devastating disease
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