BERLIN—Vitamin D increases the therapeutic effects of glucocorticoids via an mTORc1–dependent upregulation of the glucocorticoid receptor, according to a report at ECTRIMS 2018. “These data suggest that efficacy of glucocorticoids in the treatment of multiple sclerosis (MS) relapses could be improved by mTORc1 inhibition,” said lead author Maud Bagnoud, a doctoral candidate from the Department for Biomedical Research at the University of Bern in Switzerland, and colleagues.
Glucocorticoids are the mainstay in the treatment of acute MS relapses. Still, disability increases in more than 40% of patients. Ms. Bagnoud and colleagues investigated the potential of vitamin D to enhance steroid efficacy for MS relapse therapy and the mechanisms involved.
The researchers analyzed vitamin D levels using an immunoassay in patients with stable MS (n = 56), patients with relapsing glucocorticoid-responsive MS (n = 30), and patients with relapsing glucocorticoid-resistant MS (n = 24). Gene expression of human T cells (microarrays, n = 112) were correlated with 25(OH)D3 levels. Glucocorticoid receptor protein was measured using ELISA. T cell apoptosis was analyzed by FACS. Myelin oligodendrocyte glycoprotein (MOG35-55) experimental autoimmune encephalomyelitis (EAE) was performed in wild type and knockout mice with T cell specific deficiency for glucocorticoid receptor/mTORc1. The investigators analyzed the relevance of the JNK-pathway in human T cells using a competitive JNK-inhibitor (SP600125).
Patients with glucocorticoid-resistant MS had a decreased vitamin D serum level, compared with patients with glucocorticoid-responsive MS or stable MS. This decreased level of vitamin D was associated with reduced expression of the glucocorticoid receptor in T cells. In vitro, vitamin D increased the concentration of glucocorticoid receptor protein in T cells in a dose-dependent manner. Focusing on T cells donated from patients with MS during glucocorticoid-resistant relapse, this glucocorticoid receptor upregulation by vitamin D increased T cell apoptosis by approximately 10%, if treated with vitamin D and glucocorticoids, compared with glucocorticoid monotherapy. Combination therapy ameliorated EAE disease course more efficiently than monotherapies did. This effect was dependent on the presence of the glucocorticoid receptor in T cells.
On a molecular level, vitamin D inhibited mTORc1 signal transduction in murine T cells in vitro. Furthermore, hypovitaminosis D was associated with reduced expression of the archetype mTORc1 inhibitor tuberous sclerosis complex 1 in human T cells. The upregulation of the glucocorticoid receptor by vitamin D as well as the functional vitamin D/glucocorticoid synergism observed in vitro and in vivo were absent in mice with mTORc1-deficient T cells. Pharmacologic inhibition of mTORc1 by everolimus augmented the effects of glucocorticoid treatment in wild type mice during EAE even more potently than vitamin D co-administration did.
No significant changes of proliferation or apoptosis by JNK-inhibition and MP co-incubation were observed in human T cells.