Effect of CC chemokine receptor 4 antagonism on the evolution of experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS) wherein T helper (Th) 17 cells are the major pathogenic players orchestrating demyelination of axons. Recently in PNAS, Poppensieker et al. (1) documented a key role on the requirement of CC chemokine receptor 4 (CCR4) in EAE. The authors reported that CCR4 is required for GM-CSF–dependent IL-23 secretion by dendritic cells (DCs) in the CNS and for the maintenance of Th17 cells and the development of EAE. The results thus indicate that CCR4 is a potential therapeutic target in EAE, and eventually MS. Therapeutic strategies to target DC-specific CCR4 are not yet available. However, several functionally potent small molecule antagonists to CCR4 in general, irrespective of its expression on cell types, have been identified (2, 3). Therefore, we explored the therapeutic utility of antagonizing CCR4 in EAE. We induced EAE in C57BL/6 mice in three different groups by injecting myelin oligodendrocyte glycoprotein (MOG35–55) in complete Freund’s adjuvant. On the day of onset of clinical signs [day (d) 8], a group of mice were injected daily with 1.5 μg of a CCR4 antagonist, AF399/420/18025 (4-(1-benzofuran-2-ylcarbonyl)-1-{5-[4-chlorobenzyl)sulfanyl] -1,3,4-thiadiazol-2-yl}-3-hydroxy-5-(2-thienyl)-1,5- dihydro-2H-pyrrol-2-one; Formula-C …