Reduced experimental autoimmune encephalomyelitis after intranasal and oral administration of recombinant lactobacilli expressing myelin antigens.
Oral administration of autoantigens is a safe and convenient way to induce peripheral T-cell tolerance in autoimmune diseases like multiple sclerosis (MS). To increase the efficacy of oral tolerance induction and obviate the need for large-scale purification of human myelin proteins, we use genetically modified lactobacilli expressing myelin antigens. A panel of recombinant lactobacilli was constructed producing myelin proteins and peptides, including human and guinea pig myelin basic protein (MBP) and proteolipid protein peptide 139-151 (PLP(139-151)). In this study we examined whether these Lactobacillus recombinants are able to induce oral and intranasal tolerance in an animal model for multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Lewis rats received soluble cell extracts of Lactobacillus transformants intranasally three times prior to induction of EAE. For the induction of oral tolerance, rats were fed live transformed lactobacilli for 20 days. Ten days after the first oral administration EAE was induced. Intranasal administration of extracts containing guinea pig MBP (gpMBP) or MBP(72-85) significantly inhibited EAE in Lewis rats. Extracts of control transformants did not reduce EAE. Live lactobacilli expressing guinea pig MBP(72-85) fused to the marker enzyme beta-glucuronidase (beta-gluc) were also able to significantly reduce disease when administered orally. In conclusion, these experiments provide proof of principle that lactobacilli expressing myelin antigens reduce EAE after mucosal (intranasal and oral) administration. This novel method of mucosal tolerance induction by mucosal administration of recombinant lactobacilli expressing relevant autoantigens could find applications in autoimmune disease in general, such as multiple sclerosis, rheumatoid arthritis and uveitis.
Division of Immunological and Infectious Diseases, TNO-Prevention and Health (TNO-PG), P.O. Box 2215, 2301 CE Leiden, The Netherlands. cmaassen@symbigene.com
Catharina B M
CB
Maassen
Jon D
JD
Laman
Conny
C
van Holten-Neelen
Linsy
L
Hoogteijling
Lizet
L
Groenewegen
Lizette
L
Visser
Marc M
MM
Schellekens
Wim J A
WJ
Boersma
Eric
E
Claassen
D000281:Administration, Intranasal; D000284:Administration, Oral; D000818:Animals; D001324:Autoantigens / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000517:prevention & control*; D004797:Enzyme-Linked Immunosorbent Assay; D007108:Immune Tolerance; D015151:Immunoblotting; D007778:Lactobacillus / Q000235:genetics / Q000276:immunology*; D009103:Multiple Sclerosis / Q000276:immunology; D004676:Myelin Basic Protein / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew
D001324:Autoantigens; D004676:Myelin Basic Protein