Sphingosine-1-phosphate (S1P) is a lipid (fat molecule) that acts as a signaling molecule within the body, regulating various biological processes by binding to different protein receptors. S1P is known to regulate inflammation; for instance, it is important for directing where immune cells move in the body.
Modulating S1P signaling through the use of medications may be a viable strategy for the treatment of some autoimmune diseases, such as AAV. Some such medications already have been developed: most notably, fingolimod, marketed as Gilenya by Novartis, is an approved treatment for some forms of multiple sclerosis. It works by modulating the activity of some S1P receptors.
Researchers in China now evaluated whether fingolimod or other medications that act on the S1P system could help reduce the signs and symptoms of AAV in a rat model of experimental autoimmune vasculitis (EAV).
This model is created by infusing animals with the human myeloperoxidase protein, forcing their immune system to produce ANCA antibodies against this protein. These MPO-ANCA antibodies then target specific immune cells in the body, causing damage to small blood vessels.
Rats infused with human MPO quickly developed proteinuria (elevated levels of proteins in urine) and hematuria (blood in the urine), indicating kidney damage. The animals had well-established disease four weeks after this protocol was initiated. At this point, treatment with fingolimod, SEW2871, or TY52156 (also S1P receptor modulators) was administrated five times a week.
Fingolimod significantly reduced both proteinuria and hematuria, with effects being evident as early as two weeks after initiating the treatment. The other two treatments, however, had no effect on these symptoms.
Fingolimod also reduced damage in the kidneys and lungs, the most frequently affected organs in AAV. For instance, fingolimod-treated rats had significantly lower proportions of glomerular crescents, markers of kidney damage, than animals receiving a saline solution (3.0% vs. 15.1%).
In multiple sclerosis, fingolimod is believed to work primarily by “trapping” immune cells, such as T-cells and B-cells, in lymph nodes (immune organs). This prevents these immune cells from traveling elsewhere in the body and causing damaging inflammation.
Consistently with this mechanism of action, fingolimod treatment significantly reduced the amount of T-cells present in circulation and in the kidneys of the AAV rat model.
Additional experiments using cells in dishes suggested that fingolimod significantly reduces T-cells’ growth and their ability to migrate to tissues from the bloodstream.
However, fingolimod treatment did not significantly affect levels of ANCAs — the antibodies that cause damage in AAV. Antibodies are produced by B-cells, whereas T-cells have other roles in driving inflammation. As such, these results indicate that the effects of fingolimod in AAV are due primarily to the medication affecting T-cells, not B-cells.
“We show that the S1P receptor modulator FTY720 [fingolimod] is an effective treatment of established EAV, a rat model of MPO–ANCA vasculitis,” the researchers concluded. “This effect is mediated through depletion of circulating lymphocytes, reduction of renal T-cell infiltration and direct effects on T-cell proliferation, apoptosis, adhesion and migration, with little effect on the production of ANCA.”
“Already approved for use in humans, [fingolimod] shows potential as an additional therapeutic agent in AAV,” the researchers added.