Experimental autoimmune neuritis (EAN) is a CD4+ T cell-mediated inflammatory demyelinating disease of the peripheral nervous system (PNS) that serves as a model for Guillain-BarnS syndrome (GBS) in humans. Both EAN and GBS are associated with upregulated T and B cells responses to PNS myelin proteins including P2 protein, and by changes of the Thl/Th2 cell balance in favor of Thl. Here we report that EAN can be prevented by the dominant neuritogenic peptide 57-81 of the PNS P2 protein when given nasally before immunization of Lewis rats with bovine PNS myelin (BPM) + Freund's complete adjuvant (FCA). P2 peptide-tolerized rats were also resistant to EAN relapse after challenge with BPM. Tolerance to EAN in rats receiving high dose (60µg/day/rat) P2 peptide nasally was associated with specific T and B cell anergy. This was characterized by the failure of T cells to proliferate in response to PNS myelin antigens, while responsiveness to phytohemagglutinin was retained. Numbers of BPM- and P2 peptide-reactive interferon- γ mRNA expressing lymph node cells were reduced, while levels of P2 peptide-reactive interleukin 4 and transforming growth factor-β mRNA-expressing cells were markedly upregulated on day 18 post immunization in the rats receiving high dose P2 peptide nasally. Tolerance to EAN was also associated with lower CD4+ cell infiltration, low-grade inflammation, or the absence of histological evidence of EAN, as well as with low IL-2 receptor and MHC class II molecule expression within the PNS. This is the first study showing that mucosal tolerance is applicable to EAN and, as an extension, could be considered in GBS.