Antiphospholipid syndrome : discovery of a promising route to improving patient care

Work done by the teams Nephrology–Adult Transplant department of the Necker Hospital-Sick Children (AP-HP, department led by Prof Christophe Legendre) and Inserm research unit 1151 shows that the development of vascular lesions during antiphospholipid syndrome is largely associated with activation of the AKT/mTORC pathway in endothelial cells by antiphospholipid antibodies.

“When this pathway is activated, whatever the cell type, it induces proliferation and growth of the cell” explains Dr Canaud. “First of all we observed in man that this pathway was highly activated in the vessels of patients with a kidney disorder linked to antiphospholipid syndrome and in vessels of the kidney graft after transplant in patients affected by this syndrome. It is also activated in other vascular regions for an extremely severe form of this syndrome“.

The researchers confirmed in vitro that antiphospholipid antibodies were capable of activating the AKT/mTORC pathway in endothelial cells in cultures. They were later able to test in vitro the impact of different AKT/mTORC pathway inhibitors, including sirolimus, on endothelial cells exposed to antiphospholipid antibodies.

Backed by these laboratory results, the researchers observed the impact of sirolimus treatment in a group of transplant patients with antiphospholipid syndrome.

Among 37 patients with antiphospholipid syndrome, transplanted at the Necker Hospital from 2001 to 2009, 10 received sirolimus as an immunosuppressor. These ten patients, compared with the 27 patients that did not receive sirolimus but another class of immunosuppressor, were spared the recurrence of vascular lesions and saw the survival of their transplant very significantly improved.

For Dr Canaud, “For the first time, this study describes the mechanisms that lead to thickening of vessel walls in these patients.

Inhibition of the AKT/mTORC pathway, using sirolimus, makes it possible to prevent the reappearance of vascular lesions after the graft and so improve renal survival (12 years post-transplant).

This observation opens a promising therapeutic route in transplant patients with antiphospholipid syndrome, or even in patients carrying this syndrome but not transplanted”.

[1] The tunica intima is the inner layer of blood vessels, corresponding to the endothelial cells and the underlying connective tissue.