title: IDO (indolamine 2,3-dioxygenase) expression and function in the CNS.
abstract: From an immunological perspective the placenta is an allograft and therefore requires a special immune suppressive status termed immune privilege. Other organs of the body, which possess poor regenerative capacity share this special status, e.g. the brain, the eye and the gonads. The biological function of immune privilege in all these tissues is to protect them from inflammation-mediated injury. The mechanism maintaining immune privilege are poorly understood and are apparently site-specific. In the placenta, inhibition of IDO leads to spontaneous abortion, showing the crucial role of this enzyme for the maintenance of immune privilege. By catabolizing extracellular tryptophan IDO inhibits local T cell proliferation thereby preventing placental rejection. Here, we show that this mechanism can also be active in suppressing inflammatory responses in the CNS, where inflammations must be tightly regulated to prevent the loss of irreplaceable neurons. Employing RT-PCR and Western blot analysis we could show that, upon activation with the pro-inflammatory cytokine interferon-gamma, astrocytes and microglia are capable of expressing IDO in vitro and in vivo. To test the functional capacity of IDO in the CNS, we performed blockade experiments using actively induced experimental autoimmune encephalomyelitis (EAE), a T cell-mediated autoimmune disease which correlates to the human disease multiple sclerosis (MS). Inhibition of IDO activity by daily subcutaneous administration of the specific IDO inhibitor 1-methyl-DL-tryptophan during EAE significantly exacerbates EAE, shown by comparing clinical disease scores. Thus, local expression of IDO during inflammation is apparently a self-protection mechanism which limits antigen-specific immune responses in the CNS.
authors.affiliation: Campus Charité Mitte, Inst. f Anatomie, AG Zell u. Neurobiologie Philippstr. 12, 10115 Berlin, Germany. erik.kwidzinski@charite.de
authors.forename: Erik
authors.initials: E
authors.lastname: Kwidzinski
authors.forename: Jörg
authors.initials: J
authors.lastname: Bunse
authors.forename: Adam D
authors.initials: AD
authors.lastname: Kovac
authors.forename: Oliver
authors.initials: O
authors.lastname: Ullrich
authors.forename: Frauke
authors.initials: F
authors.lastname: Zipp
authors.forename: Robert
authors.initials: R
authors.lastname: Nitsch
authors.forename: Ingo
authors.initials: I
authors.lastname: Bechmann
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology; D002490:Central Nervous System / Q000201:enzymology* / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma / Q000494:pharmacology; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000201:enzymology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins; D014364:Tryptophan / Q000378:metabolism; D014366:Tryptophan Oxygenase / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D012333:RNA, Messenger; D011994:Recombinant Proteins; D007371:Interferon-gamma; D014364:Tryptophan; D014366:Tryptophan Oxygenase