Pioglitazone reduces the transmigratory capacity of activated T cells in an in-vitro model of the blood-brain-barrier

The peroxisomal proliferator-activated receptor gamma (PPARg) belongs to a group of ligand-activated transcription factors expressed in lymphocytes, monocytes, dendritic cells and endothelial cells. Several antiinflammatory and antiproliferative effects of PPARg agonists on lymphocytes from multiple sclerosis (MS) patients have already been characterized. Interestingly, oral treatment with PPARg agonists like pioglitazone ameliorate the clinical course of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In pioglitazone-treated animals, brains and spinal cord sections exhibit greatly decreased perivascular inflammation and a massive reduction in lymphocyte infiltration of the brain parenchyma.

As the penetration of the blood-brain-barrier (BBB) by activated T cells is one of the crucial steps in the pathogenesis of MS, and the results of several EAE studies suggest an influence of PPARg agonists on the ability of activated T cells to pass the BBB, we wanted to investigate the effects of pioglitazone on the transmigratory capacity of activated T cells. We used an in vitro model of the BBB consisting of a monolayer of murine brain endothelial cells seeded on a laminin-coated polycarbonate membrane transwell system. After 2 days, the transmigratory capacity of an antigen-specific T cell line was assessed in the presence of pioglitazone. Additionally, we investigated the influence of pioglitazone on the adhesion of activated T cells to the brain-derived endothelial cell monolayer.

Pioglitazone treatment significantly reduced the transmigratory activity of T cells in a concentration-dependent manner, with a maximum effect observed at a concentration of 10µM pioglitazone. Similarly, the adhesion of activated T cells to brain derived endothelial cells was significantly reduced by pioglitazone treatment.

These results demonstrate that pioglitazone reduces the capacity of activated antigen-specific T cells to adhere to and migrate through brain derived endothelial cells. This mechanism presumably is at least partly responsible for the protective effects of PPARg agonists on the development of EAE, and contributes to previously characterized antiinflammatory effects of PPARg agonists on T cells, thus enhancing the potential value of these substances for the treatment of MS.