Treatment of experimental allergic encephalomyelitis (EAE) induced by guinea pig myelin basic protein epitope 72-85 with a human MBP87-99 analogue and effects of cyclic peptides

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory and demy elinating disease of the central nervous system and is an animal model of m ultiple sclerosis (MS). In the present report, a linear analogue and a seri es of cyclic semi-mimetic peptides were designed and synthesized based on t he human myelin basic protein (MBP87-99) epitope (Val(87)-His-Phe-Phe-Lys-A sn-Ile-Val-Thr-Pro-Arg-Thr-Pro(99)) and on Copolymer I (a mixture of random polymers of Ala, Gln, Lys and Tyr used to treat MS). These analogues were designed looking for suppressors of EAE induced by guinea pig MBP72-85 epit ope (Gln-Lys-Ser-Gln-Arg-Ser-Gln-Asp-Glu-Asn-Pro-Val) in Lewis rats. The li near analogue [Arg(91),Ala(96)]MBP87-99, in which Arg substitutes Lys(91) a nd Ala substitutes pro(96), was found to be a strong inhibitor which when a dministered to Lewis rats together with the encephalitogenic agonist MBP72- 85 completely prevented the induction of EAE. In contrast, three N- and C-t ermini amide-linked cyclic semi-mimetic peptides, [cyclo-Phe-Arg-Asn-Ile-Va l-Thr-Ala-Acp (1), cyclo-Phe-Ala-Arg-Gln-Acp (2), cyclo-Tyr-Ala-Lys-Gln-Acp (3)] as well as a Lys side chain and C-terminous cyclic semi mimetic pepti de cyclo(lys, Acp)-Phe-Lys-Asn-Ile-Val-Thr-Ala-Acp (4) which contain segmen ts of MBP87-99 Or are constituted from immunophoric residues of copolymer I , were ineffective in inducing or inhibiting EAE in Lewis rats. However co- injection of cyclic analogues with MBP72-85 delayed the onset of EAE indica ting a modulatory effect on the EAE activity of MBP72-85 These findings sug gest that molecule length, size of cyclic moiety and backbone conformation are important elements for immunogenic activity. Moreover blockade of MBP72 -85 induced EAE by the unrelated peptide [Arg(91),Ala(96)]MBP87-99 could in dicate that the mechanism of inhibition is not due to binding competition b ut rather due to the delivery of a negative signal by the antagonist which overcomes the agonist response possibly through the activation of antigen s pecific regulatory T cells. (C) 2000 Elsevier Science Ltd. All rights reser ved.