Prostaglandins and inhibitors of arachidonate metabolism suppress experimental allergic encephalomyelitis.
Experimental allergic encephalomyelitis (EAE) is an autoimmune inflammatory disease of the central nervous system (CNS). It is an animal model of post-infectious encephalomyelitis and multiple sclerosis (MS). Acute EAE is mediated by macrophages and by T helper 1 (Th1) lymphocytes directed against brain antigens. Inflammation in EAE could potentially be modified by prostaglandins (PG) secreted by blood monocytes (Mo) and brain glial cells. PGE elevates cAMP, which inhibits Mo function and selectively blocks secretion of cytokines by Th1 cells. In the present study, we found that a long-acting PGE1 analogue (LAPGE) inhibited clinical and histological EAE. Indomethacin (INDO) also suppressed active EAE. The combination of INDO plus LAPGE inhibited disease further, possibly by allowing LAPGE to function unopposed by immunostimulatory PG. EAE was suppressed when these agents were administered from the time of immunization or from the onset of clinical disease. The combination of INDO plus LAPGE also inhibited delayed-type hypersensitivity (DTH) reactions to myelin basic protein (MBP), and diminished in vitro lymphocyte responses to mitogens and MBP. PGE analogues and modifiers of arachidonate metabolism block autoimmune responses to brain antigens in vitro and in vivo, and may ameliorate inflammatory and autoimmune diseases of the brain and other organs.
Reder
A T
AT
Department of Neurology, University of Chicago, IL 60637.
Thapar
M
M
Sapugay
A M
AM
Jensen
M A
MA
D000527:Alprostadil / Q000031:analogs & derivatives; D000818:Animals; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors*; D004338:Drug Combinations; D004487:Edema / Q000209:etiology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D006968:Hypersensitivity, Delayed / Q000150:complications / Q000276:immunology / Q000473:pathology; D007213:Indomethacin / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D016595:Misoprostol / Q000494:pharmacology; D004676:Myelin Basic Protein / Q000276:immunology; D011453:Prostaglandins / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew
D004338:Drug Combinations; D004676:Myelin Basic Protein; D011453:Prostaglandins; D016595:Misoprostol; D016718:Arachidonic Acid; D000527:Alprostadil; D007213:Indomethacin