Symposium: Nutrients, Nuclear Receptors, Inflammation, and Immunity Nuclear Receptors and Autoimmune Disease: The Potential of PPAR Agonists to Treat Multiple Sclerosis 1,2 Michael K. Racke,* y3 Anne R. Gocke,* Mark Muir,* Asim Diab,* Paul D. Drew,** and Amy E. Lovett-Racke* * Department of Neurology and the y Center for Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390 and ** Department of Neurobiology and Developmental Sciences, University of Arkansas for the Medical Sciences, Little Rock, AR 72205 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 PPARg in EAE and observed that administration of the PPARg agonist 15-deoxy- D 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 PPARa 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 PPARa 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 PPARa 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. J. Nutr. 136: 700–703, 2006. KEY WORDS:  PPAR  autoimmunity  multiple sclerosis  cytokines  nuclear receptors Approximately 350,000 people in the United States have physician-diagnosed multiple sclerosis (MS) 4 (1,2). Following trauma it is the next leading cause of neurologic disability in the United States in young adults, and most patients suffer from the effects of MS for most of their adult life. The cause of MS remains unknown, but because the disease involves perivascu- lar mononuclear cell infiltrates and demyelination [features also characteristic of experimental autoimmune encephalomyelitis (EAE)], an autoimmune process is hypothesized to be involved in disease pathogenesis (3,4). There are now five drugs approved for use in the treatment of MS by the FDA, however, none of these agents are a cure for the disease, and the need for better treatment strategies for MS remains (5–8). In addition, with the withdrawal of drugs such as nataluzimab and its potential for infectious toxicity, it is clear that long-term safety is an important consideration for new MS therapies. Relevance of EAE to multiple sclerosis. Several animal models have been used to study MS (3,4). Our laboratory has exclusively used the murine model of EAE for a number of reasons. Murine EAE results in a relapsing-remitting disease, similar to the early phase of disease for most MS patients. In chronic murine EAE, the pathology observed in the white matter shows demyelination that is reminiscent of the pathol- ogy seen in the central nervous system of humans with MS. With the advent of transgenic and homologous recombination technology, it is increasingly clear that many powerful molec- ular tools are becoming available for studying the immune response in pathologic processes such as EAE. 1 Published in a supplement to The Journal of Nutrition. Presented at the ‘‘Nutrients, Nuclear Receptors, Inflammation, and Immunity’’ symposium held April 3, 2005 at Experimental Biology 2005 in San Diego, California. The symposium was sponsored by the National Institutes of Health Office of Dietary Supplements, the U.S. Department of Agriculture, Wyeth Nutrition, and the American Society for Nutrition. The symposium was chaired by Charles Stephensen of the U.S. Department of Agriculture Western Human Nutrition Research Center at the University of California, Davis, and by Margherita Cantorna of the Nutrition Department at the Pennsylvania State University. 2 This work was supported by grants from the National Institutes of Health and National Multiple Sclerosis Society (M.K.R. and P.D.D.). This work was also supported by a Harry Weaver Neuroscience Scholarship from the National Multiple Sclerosis Society (A.E.L.R.) and a Doris Duke Predoctoral Fellowship (M.M.). 3 To whom correspondence should be addressed. E-mail: michael.racke@ utsouthwestern.edu. 4 Abbreviations used: CFA, complete Freund’s adjuvant; EAE, experimental autoimmune encephalomyelitis; GATA-3, GATA binding protein-3; MBP, myelin basic protein; MS, multiple sclerosis; NF-kB, nuclear factor-kB; PPAR, peroxisome proliferator-activated receptor; STAT, signal transducing activator of transcription; Th, T helper; TNF, tumor necrosis factor. 0022-3166/06 $8.00 Ó 2006 American Society for Nutrition. 700 by guest on April 17, 2016 jn.nutrition.org Downloaded from