Scientists from the Netherlands have now shown that P-gp may play a key role in multiple sclerosis (MS). In MS, autoreactive myelin-specific T helper (Th) cells – which are primed in the periphery by antigen-presenting dendritic cells (DCs) – cause extensive destruction of myelin sheaths and axonal loss. The team found that both DC maturation and T-cell stimulatory capacity were severely impaired in P-gp knockout mice (Mdr1a/1b-/-) which showed less severe clinical symptoms of experimental autoimmune encephalomyelitis (EAE) following administration of recombinant myelin oligodendrocyte glycoprotein (rMOG) than wild type animals. The observed differences in clinical symptoms were associated with decreased demyelination in the brains of the knockout animals and reduced brain inflammation. Following immunisation with rMOG, secretion of Th1 cytokines, IFN-γ and TNF-α and Th2 cytokines, IL10 and IL5, by lymph node cells was significantly reduced in the Mdr1a/1b-/- mice compared with wild type animals whereas no changes were observed in the secretion of the Th17 cytokine, IL-17. Since P-gp did not affect the ability of T-cells to become activated, the authors propose that the observed differences in T-cell responses are likely mediated by regulation of cytokine secretion by DCs.
The study, which is published in PLoSone, highlights a novel immunomodulatory role for P-gp and may provide new opportunities to treat immune-related or inflammatory diseases.