Immunological Effects of Lithium in Progressive Multiple Sclerosis

Background: Multiple sclerosis (MS) is an immune-mediated progressive disease of the central nervous system (CNS) which is partly modifiable by immune modulating drugs.

Lithium (Li) ameliorates murine experimental autoimmune encephalomyelitis (EAE), putatively by immunological effects downstream of its primary mechanism of action, the inhibition of glycogen synthase kinase 3 (GSK3). In a pilot trial of Li for progressive MS, Li was associated with trends towards decreased brain atrophy and EDSS stabilization over one year, and improved scores on the Beck Depression Inventory and the Mental Health sub score of the MSQOL-54. These effects are consistent with the known effects of Li on neuroprotection and mood.

Objectives: In this pilot trial, we examined immune effects attributable to Li treatment.

Methods: Blood samples from MS patients were drawn at baseline and twice during each phase (Li-treatment and observation) of this 2-year crossover trial. Peripheral blood mononuclear cells (PBMCs) were isolated. One aliquot of PBMCs was lysed in lysis buffer containing protease and phosphatase inhibitors. PBMCs and cell lysates were frozen, and stored at -80⁰C, until the study conclusion for analysis. PBMC lysates were immunoblotted for markers of GSK3α and GSK3β inhibition (phospho-Ser21-GSK3α, phospho-Ser9-GSKβ), total GSK3α, total GSK3β, and β-Actin. Phenotypic and functional properties of PBMCs subsets, before and after Li treatment, were analyzed by multiparametric flow cytometry staining panels. We interrogated CD4+ and CD8+ T cells, Tfh cells, B cells, and monocytes, for changes in proportion by both surface markers and expression of intracellular cytokines (IFN-y, IL-17, IL-4, and IL-10).

Results: Li treatment increased serine phosphorylation of both GSK3α and GSK3β, indicating inhibition of the enzyme. Flow cytometric analysis revealed a decreased in frequency of CD8+ T cells in PBMCs of patients during Li treatment respect to the observation phase. The proportion of IFN-y expressing CD8+ T cells and IL-17 expressing CD4+ T cells were reduced in the Li-treatment phase

Conclusions: Our results demonstrate that low-dose Li treatment in MS progressive patients inhibits the pro-inflammatory enzyme GSK3. Our FACS analysis reveal that lithium treatment has an anti-inflammatory effect on some subpopulations of mononuclear cells, by decreasing the proportions of inflammatory effector cells. These results indicate that Li may be therapeutically relevant in MS.