NITRIC-OXIDE IS A POTENTIAL DOWN-REGULATING MOLECULE IN AUTOIMMUNE-DISEASE - INHIBITION OF NITRIC-OXIDE PRODUCTION RENDERS PVG RATS HIGHLY SUSCEPTIBLE TO EAE

Rat strains vary in their susceptibility to experimental autoimmune en cephalomyelitis (EAE) and in many cases, factors other than MHC antige ns are thought to play a role in this. We found that PVG rats, which h ave a very low susceptibility to EAE, were rendered highly susceptible to clinical disease when treated with N-methylarginine (NMA) an inhib itor of nitric oxide synthase (NOS). The clinical course of the ensuin g disease in NMA-treated PVG rats was in most cases fulminating in nat ure and accompanied by some mortality. Following immunisation with mye lin basic protein (MBP)-complete Freund's adjuvant (CFA), PVG rats dev eloped higher serum levels of the surrogate markers of nitric oxide pr oduction, reactive nitrogen intermediates (RNI; nitrite and nitrate), than did their Lewis counterparts. This in vivo finding was reflected in vitro, where the levels of RNI produced in 24, 48 and 72 h IFN-gamm a-stimulated spleen cell cultures for PVG rats were significantly high er than those for Lewis rats. A mechanism by which increased NO produc tion might protect PVG rats against clinical EAE was suggested by the finding that lymph node cells, isolated from NMA-treated MBP-immunised PVG rats, proliferated in response to MBP at a rate approximately 3 X greater than those from MBP-immunised, saline treated rats. Thus, the greater number of MBP-specific T cells generated in the NOS inhibitor -treated vs, untreated rats could account for their increased suscepti bility to developing clinical EAE. The findings in this study suggest that NO plays a role in protecting PVG rats against developing EAE. (C ) 1998 Elsevier Science B.V. All rights reserved.