#ECTRIMS2018 — Vitamin D May Boost Glucocorticosteroid Effectiveness in MS Relapses, Study Suggests
Vitamin D may increase the therapeutic benefits of glucocorticosteroids (GCs) for multiple sclerosis (MS) through a protein complex called mTORc1, according to a study in a mouse model and in cells from MS patients.
The study, “Vitamin D augments glucocorticosteroid efficacy via inhibition of mTORc1,” was presented Wednesday at the 34th congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), which is taking place through Friday in Berlin.
GCs are typically used in the treatment of acute MS relapses. However, more than 40 percent of these patients experience increased disability despite the treatment.
Aiming to find ways to boost the effectiveness of GCs, an international team of researchers from Switzerland, Australia, Germany, and the U.S. explored the potential of vitamin D, as well as its underlying mechanisms, in easing MS relapses.
Vitamin D levels were analyzed in 56 stable, 30 relapsing and GC-responsive, and 24 relapsing and GC-resistant (non-responsive) MS patients. Gene expression of immune T-cells were correlated with the levels of 25(OH)D3, an indicator of vitamin D status in the body. The amount of glucocorticoid receptor and the extent of T-cell-apoptosis — which refers to “programmed” cell death, as opposed to death caused by injury — were also assessed.
The team used a mouse model of MS with or without the glucocorticoid receptor and mTORc1 — which responds to GC treatment — specifically in T-cells. In addition, the role of the JNK signaling pathway — which inhibits glucocorticoid receptor-mediated gene expression and is a major target of GC’s anti-inflammatory effect — was analyzed in human T-cells using a JNK-inhibitor known as SP600125.
Results revealed that the serum levels of vitamin D were lower in GC-resistant MS patients than in GC-responsive and stable MS patients. This finding was associated with a lower production of glucocorticoid receptor in T-cells.
In vitro experiments in T-cells showed that vitamin D increases the concentration of glucocorticoid receptor in a dose-dependent manner.
Researchers also found that, in T-cells from MS patients during GC-resistant relapse, a combination of vitamin D and GC boosts T-cell apoptosis by approximately 10% in comparison to stand-alone GC therapy. The combination approach also eased the disease course in mice more efficiently than treatment with either approach alone, a benefit dependent on the presence of glucocorticoid receptors in T-cells.
On a molecular level, vitamin D inhibited mTORc1 signaling in mouse T-cells. Hypovitaminosis D, or vitamin D deficiency, was correlated with lower production of an mTORc1 inhibitor known as tuberous sclerosis complex 1 in human T-cells.
Interestingly, a vitamin D-induced increase in glucocorticoid receptor levels, as well as the added benefits of using both vitamin D and GC, were absent in mice with no mTORc1 in T-cells, suggesting this molecule plays an important role in vitamin D and GC effects.
Furthermore, mTORc1 inhibition with the chemotherapy agent everolimus (marketed as Afinitor) enabled an even more potent increase in GC effects in mice with MS than with vitamin D. Conversely, JNK inhibition did not alter the proliferation or apoptosis in human T-cells.
Overall, the team concluded that vitamin D “increases therapeutic effects of GCs via a mTORc1 dependent upregulation of the GR [glucocorticoid receptor]. These data suggest that efficacy of GC in treatment of MS relapses could be improved by mTORc1 inhibition.”
Of note, nine of the study’s authors received research or travel grants, speaker honoraria, or compensations from several companies, including Novartis, Biogen, Merck, Almirall, and Sanofi Genzyme.