title: Eicosenoids Modify Experimental Allergic Encephalomyelitis.
abstract: Experimental allergic encephalomyelitis (EAE) is an autoimmune inflammatory disease of the brain and spinal cord. It is an animal model of postinfectious encephalomyelitis and multiple sclerosis (MS). In EAE and in MS, monocytes and Th1 lymphocytes penetrate the blood-brain barrier, and the ensuing inflammation causes demyelination and death of oligodendroglia. PGE is a product of blood Mo and of brain glial cells that affects immune regulation. PGE and other cAMP agonists inhibit monocyte function and secretion of cytokines by Th1 cells. However, they have minimal effects on some cytokines secreted by Th2 cells. We hypothesized that eicosenoids would inhibit central nervous system inflammation mediated by Th1 cells. We found that misoprostol, a long-acting PGE1 analog, inhibited clinical and histological signs of moderately severe EAE in Lewis rats. Indomethacin also suppressed EAE and enhanced the LAPGE effect. Both agents suppressed EAE when administered either from the time of immunization or from the onset of clinical disease. The combination of misoprostol and indomethacin inhibited delayed-type hypersensitivity reactions to MBP (a Th1 response). These agents also inhibited in vitro lymphocyte proliferation to mitogens and MBP. Leukotrienes (LKT) elevate intracellular cGMP and amplify immune responses, the opposite of cAMP agonists. We found that LKT synthesis inhibitors blocked EAE, presumably by lowering levels of cGMP in inflammatory cells. Reduction of LKT synthesis enhanced the effects of misoprostol plus indomethacin on EAE. PGE analogs, indomethacin, and inhibitors of LKT synthesis block autoimmune responses to brain antigens in vitro and in vivo. Modification of intracellular cAMP and cGMP levels with these agents may ameliorate inflammatory and autoimmune diseases.
authors.affiliation: The University of Chicago Department of Neurology, and the Brain Research Institute Chicago, USA.
authors.forename: Anthony T.
authors.initials: AT
authors.lastname: Reder
authors.forename: Manjula
authors.initials: M
authors.lastname: Thapar
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Sapugay
authors.forename: Mark A.
authors.initials: MA
authors.lastname: Jensen