A small-molecule inhibitor of macrophage migration inhibitory factor for the treatment of inflammatory disease.
Multiple sclerosis (MS) is a chronic, debilitating disease of the central nervous system (CNS) characterized by demyelination and axon loss. The proinflammatory cytokine macrophage migration inhibitory factor (MIF) has been shown to be elevated in the cerebrospinal fluid of patients during relapses. The purpose of this study was to evaluate a new small-molecule inhibitor of MIF and its ability to reduce the severity of an animal model of MS, experimental autoimmune encephalomyelitis (EAE). We utilized 2 structurally related isoxazolines, which show in vitro inhibition of MIF tautomerase activity. We found that administration of an inhibitor of MIF to mice with established EAE immediately reduced the severity of clinical signs and expanded a population of regulatory T lymphocytes. We also noted that the inhibitor reduced relapses of disease in a relapsing/remitting model of EAE. An analysis of leukocyte migration into the brain revealed that administration of inhibitor reduced entry of these cells. No effects on inflammatory cytokine production or T-cell activation in the periphery were noted. From these studies, we conclude that a small-molecule inhibitor of MIF reduces the severity of EAE and prevents access of immune cells into the CNS, which could be of therapeutic relevance to MS.
Kithcart
Aaron P
AP
Department of Molecular Virology, Immunology, and Molecular Genetics, The Ohio State University, Columbus, OH 43210, USA.
Cox
Gina M
GM
Sielecki
Thais
T
Short
Abigail
A
Pruitt
James
J
Papenfuss
Tracey
T
Shawler
Todd
T
Gienapp
Ingrid
I
Satoskar
Abhay R
AR
Whitacre
Caroline C
CC
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000473:pathology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000473:pathology; D005434:Flow Cytometry; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D007555:Isoxazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use*; D013116:Spinal Cord / Q000473:pathology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D000893:Anti-Inflammatory Agents; C000598334:CPSI-1306; D007555:Isoxazoles; D008263:Macrophage Migration-Inhibitory Factors; D009025:Morpholines; D019010:Vascular Cell Adhesion Molecule-1