Nuclear receptors and autoimmune disease: the potential of PPAR agonists to treat multiple sclerosis

Abstract

Experimental autoimmune encephalomyelitis (EAE) is a T-cell-mediated, autoimmune disorder characterized by central nervous system inflammation and demyelination, features reminiscent of the human disease, multiple sclerosis (MS). Prior work in the EAE model has suggested that encephalitogenic T cells are of the T helper (Th)-1 phenotype. Our group has performed several studies in the EAE model that suggest that a strategy for treating autoimmune disorders is to convert the pathogenic cells from the Th1 to Th2 phenotype. Peroxisome proliferator-activated receptors (PPARs) are members of a nuclear hormone receptor superfamily that include receptors for steroids, retinoids, and thyroid hormone, all of which are known to affect the immune response. Recently, we examined the role of PPARgamma in EAE and observed that administration of the PPARgamma agonist 15-deoxy-Delta(12,14) prostaglandin J2 exerted a significant therapeutic effect predominantly by inhibiting the activation and expansion of encephalitogenic T cells. One potential advantage in studying PPARalpha agonists is that they have been very well tolerated when used in humans to treat conditions such as elevated triglycerides. Building on prior work in immune deviation and with PPAR agonists, we have demonstrated that PPARalpha agonists can alter the cytokine phenotype of myelin-reactive T cells, alter their encephalitogenicity, and be useful in the treatment of EAE. The fact that PPARalpha agonists have been used as therapeutic agents in humans to treat metabolic conditions for over 25 years with little toxicity makes them attractive candidates for use as adjunctive therapies in MS.

FIGURE 1

Transcriptional regulation of the differentiation of Th1 cells. IL-12 activates the STAT4 pathway while IFN-γ activates the STAT1 or T-bet pathway. It is unclear where PPARs regulate these pathways at a molecular level.

FIGURE 2

Transcriptional regulation of the differentiation of Th2 cells. IL-4 turns on the STAT6 pathway and GATA-3. It is unclear where PPARs such as PPARα turns on Th2 differentiation.

FIGURE 3

Gemfibrozil increases IL-4 secretion by a human T-cell line. The MBP-specific T-cell line was generated by weekly stimulation with antigen in the presence or absence of gemfibrozil (100 μM). IL-4 was measured at 48 h time point by ELISA. Means of quadruplicate cultures are shown. SD were <10% of the mean.