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The purpose of the present study was to develop a peptide fortreatment of multiple sclerosis (MS). We have tested the effectof a novel antiinflammatory peptide (KGHYAERVG, termed IIIM1)on experimental autoimmune encephalitis (EAE), an animal modelof MS. Our findings demonstrate significant reduction in neurologicalscore following oral administration of IIIM1, as compared tothe control groups received the vehicle (saline). Structuralstudies revealed that the entire peptide is required for activity.The peptide caused significant reduction in IL17, interferongamma and IL12 production by isolated splenocytes and concomitantelevation of antiinflammatory cytokines. IIIM1 elevated T regulatorycells (Tregs, CD4+CD25+FoxP3+) in brain and spleen of EAE mice.Similar proliferative effect was observed in isolated humanand mouse Tregs in vitro. Stimulation of Tregs by IIIM1 causedproduction of a new peptide termed RA1 present in Oryza SativaJaponica group. This Japanese rice peptide ameliorated neurologicalsymptoms in the EAE model. Similar beneficial effect was observedupon oral administration of an extract of Japanese rice. Inconclusion, oral treatment with IIIM1 ameliorates EAE symptomsvia stimulation of Tregs to proliferate and produce RA1 whichreduces EAE symptoms. These findings may explain the relativelylow prevalence of MS in Japan and other Japanese rice-eatingpopulations. (This work was supported in part by The IsraelScience Foundation grant 747/05).