Suppression Of Eae In The Lewis Rat By Treatment With Neuroantigen-containing Liposomes

Treatment of Lewis rats with intracardiac injections of neuroantigen-containing liposomes significantly reduced the clinical severity of spinal cord-induced experimental allergic/autoimmune encephalomyelitis (EAE). Liposomes containing myelin basic protein (MBP), galactocerebroside (GC), or MBP + GC were effective in this respect, while liposomes containing proteolipid protein were not. The best protection was afforded by liposomes composed of whole myelin, as these ameliorated both the acute and relapsing phases of the disease, with a concomitant reduction in CNS pathology.;Neuroantigen-specific proliferative responses of lymphnode cells (LNC) taken from liposome-treated rats were markedly attenuated in comparison to control LNC, while delayed type hypersensitivity (DTH) reactions were not greatly diminished. In vitro-activated LNC from myelin liposome-treated rats exhibited decreased ability to transfer disease passively. Phenotypic analysis of LNC after incubation with Ag indicated a decreased proportion of CD4{dollar}\sp{lcub}+{rcub}{dollar} cells and an increased proportion of B cells in cultures from treated as compared to control rats, which might account for their lowered encephalitogenicity. Prior to disease onset, serum anti-myelin Ab levels were slightly elevated in myelin liposome-treated rats over controls, but were clearly depressed during the disease process. These findings are discussed in relation to proposed mechanism(s) of liposome-mediated suppression of EAE.;Spleen cells (SPC) from both liposome-treated and control rats often exhibited a decreased ability to proliferate in response to neuroantigen, and poor proliferation corresponded to the presence of Ag-nonspecific inhibitory cells. This inhibition was determined to be a result of nitric oxide production by resident macrophages; significant levels of nitrite (a breakdown product of nitric oxide) were detected in suppressed cultures; N{dollar}\sp{lcub}\rm g{rcub}{dollar}-monomethyl-L-arginine (an inhibitor of nitric oxide synthase) restored proliferation; and proximity of inhibitory and responder cell populations was necessary for delivery of the suppressive signal. Although SPC from immunized rats had greater propensity to produce nitric oxide, SPC from naive rats, at higher numbers, also liberated suppressive amounts of nitric oxide. Amongst several cytokines and LPS, only IFN-{dollar}\gamma{dollar} was able to enhance nitric oxide production by adherent SPC, suggesting that T cells, through release of IFN-{dollar}\gamma{dollar} may stimulate nitric oxide production by Ag-presenting macrophages, and thereby limit their own proliferation.