Background and Aims

It is well established that the humoral immunity in antiphospholipid syndrome (APS) is presented by circulating pathogenic anti-β2GPI autoantibodies. These antibodies play a major role in the disease pathogenesis by targeting mainly domain I of the β2GPI protein. In the current trial, we had orally administered a domain-I derivative of the β2GPI molecule, in order to evaluate a new therapeutic approach: induction of oral tolerance in a mouse model of APS.

Methods

BALB/c mice immunized with β2GPI, were fed with either domain-I, domain-V or complete β2GPI molecule.

Results

β2GPI immunized mice developed experimental APS which were fed with domain-I significantly had decreased fetal loss (p<0.004), a lower size of thrombi (p<0.001) and lower circulating anti-β2GPI Abs in comparison to mice fed with domain-V or PBS (p<0.002). Likewise, Domain-I
fed mice had a lowered inflammatory response, exhibited by decreased expression of inflammatory cytokines (IFNγ, IL-6, IL-17) and elevated production of IL-10 anti-inflammatory cytokine by splenocytes. Moreover, the anti-inflammatory response in the domain-I fed APS mice was associated with alterations in circulating miRNAs, which is associated with immunomodulation of the immune network.

Conclusions

Our results show that DI-β2GPI fed APS mice developed tolerance scenario manifested by a reduction in fetal loss, thrombi size, inhibition of inflammatory cytokine production and upregulation of IL-10 and T regulatory cells. This sequence of events is associated with circulating plasma miRNA related to the immune network. Therefore we propose the DI-β2GPI derivative treatment for patients with APS.

Background and Aims

The role of helminth treatment in autoimmune diseases is constantly growing. Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease with challenging treatment options. Tuftsin phosphorylcholine (TPC) is a novel helminth-based compound that modulates the host immune network.

This study was conducted to evaluate the potential value of TPC in ameliorating lupus nephritis in a murine model and specifically to compare the efficacy of TPC to the existing first-line therapy for SLE: corticosteroids (methylprednisolone).

Methods

Lupus-prone NZBxW/F1mice were treated with TPC (5 µg/mouse), methylprednisolone (MP; 5mg/body weight) or PBS (control) three times per week once glomerulonephritis, defined as proteinuria of grade > 100 mg/dL, was established. Levels of anti-dsDNA autoantibodies were evaluated by ELISA, splenic cytokines were measured in-vitro, and the kidney microscopy was analyzed following staining.

Results

TPC and MP treatments significantly improved lupus nephritis and prolonged survival in NZBxW/F1 mice. TPC-treated mice showed a significantly decreased level of proteinuria (p<0.001) and anti-dsDNA antibodies (p<0.001) as compared to PBS-treated mice. Moreover, TPC and MP inhibited the production of the pro-inflammatory cytokines IFN-γ, IL-1β, and IL-6 (p<0.001) and enhanced expression of the anti-inflammatory cytokine IL-10 (p<0.001). Finally, microscopy analysis of the kidneys demonstrated that TPC-treated mice maintained normal structure equally to MP-treated mice.

Conclusions

This data indicates that the small molecule named TPC hinders lupus development in genetically lupus-prone mice equally as methylprednisolone in most of the cases. Hence, TCP may be employed as a therapeutic potential for lupus nephritis.