An interesting study conducted in mice has identified a new molecule involved in the immune system’s response to infused factor VIII. It is a particular membrane receptor, i.e. a molecule that is located on the outer surface of a cell and acts as a kind of sensor, known as stabilin-2. This molecule has been identified on the surface of certain immune system cells, and it is able to recognise and bind with the factor VIII-vWF (von Willebrand Factor) complex. The binding between stabilin-2 and the factor VIII-vWF complex causes the immune system cell to ingest and destroy the complex by a process called phagocytosis. This phenomenon has two important consequences:
- the triggering of an immune reaction against factor VIII, which results in the production of inhibitors that neutralise the effects of replacement therapy;
- the elimination of factor VIII infusion from circulating blood, which significantly reduces the effectiveness of the therapy.
The researchers noted that mutant mice, in which stabilin-2 is not produced, are less exposed to inhibitory risk. In these mice, factor VIII also remains in the bloodstream for longer, thereby prolonging its effectiveness.
Similar results were also obtained in normal mice, i.e. those expressing stabilin-2, by injecting a factor VIII-vWF concentrate that also contained hyaluronic acid. The latter, in fact, binds to stabilin-2 and keeps it “occupied”, thereby allowing the factor VIII-vWF complex to continue circulating undisturbed in the bloodstream.
Although the details and implications of this mechanism have not yet been clarified, stabilin-2 appears to be a promising target for future studies aimed not only at decreasing the risk of inhibitor onset, but also at increasing the half-life of factor VIII infusion.
- Swystun L. L. et al. The endothelial cell receptor stabilin-2 regulates VWF-FVIII complex half-life and Immunogenicity. J Clin Invest., 2018. 128(9):4057-4073