Therapeutic effect of lithium in EAE: Effects on dendritic cells and encephalitogenic activity of T cells. (96.16)

Abstract

Abstract We have reported that the GSK3 inhibitor, lithium, is therapeutic in acute and relapsing remitting EAE. We have now determined that lithium treatment is effective in attenuating EAE induced by Th1 encephalitogenic T-cells but not Th17 cells. These results were obtained from passive transfer experiments in which encephalitogenic Th1 or Th17 cells were transferred into lithium-treated or untreated naïve recipients. Consistent with this observation, lithium treatment was also ineffective in inhibiting EAE in IFN-γR1-/- mice. Various experiments indicated that the primary target of lithium therapy in vivo were cells of the innate immune system such as, dendritic cells (DC) rather than T-cells. Using primary dendritic cells obtained from spleens and lymph nodes or bone marrow derived DC (BMDC), we have determined that lithium does not affect LPS or CpG-induced maturation of DC. Remarkably, lithium treated DC were as or more efficient than untreated DC in their ability to process and present ovalbumin to OTII T-cells or MOG35-55 peptide to T-cells from 2D2 TCR transgenic mice. These observations raise the possibility that lithium-treatment of DC alters the chemokine and cytokine profile involved in migration and/or Th-subset specific differentiation. Overall, our findings that pharmacological inhibition of GSK3 is effective in Th1 EAE but not Th17 EAE has crucial implications for identifying and treating MS patients.