title: Oral administration of cholera toxin B subunit conjugated to myelin basic protein protects against experimental autoimmune encephalomyelitis by inducing transforming growth factor-beta-secreting cells and suppressing chemokine expression.
abstract: The efficacy and mechanism of immunosuppression against experimental autoimmune encephalomyelitis (EAE) by oral low-dose administration of myelin basic protein (MBP) conjugated to cholera toxin B subunit (CTB) were investigated in Lewis rats immunized with MBP together with complete Freund's adjuvant 4 days before the start of treatment. Oral treatment with CTB-MBP conjugate gave almost complete protection against disease, an effect that was totally abrogated by including a low dose of cholera holotoxin (CT). The protection by CTB-MBP was associated with a dramatic reduction in the number of leukocytes staining for CD4, CD8, IL-2R or MHC class II in the spinal cord as examined by immunohistochemistry. The mRNA expressions of T(h)1 cytokines IFN-gamma, IL-12 and tumor necrosis factor-alpha, as well as of chemokines monocyte chemotactic protein (MCP)-1 and RANTES in the spinal cord were also reduced by 76-94%, as assessed by in situ hybridization. In contrast, transforming growth factor (TGF)-beta mRNA-expressing cells were strongly increased in the spinal cord from animals treated orally with the CTB-MBP conjugate. In the draining peripheral lymph nodes, the number of MBP-specific TGF-beta mRNA-expressing cells was also increased, whereas there was a decrease in cells expressing T(h)1 or T(h)2 cytokine mRNA. Protection against EAE could be transferred by injection of cells from the mesenteric lymph nodes of animals fed with CTB-MBP into naive animals exposed to encephalitogenic T cells. The results indicate that the protective anti-inflammatory effect by oral treatment with CTB-MBP conjugate is, to a large extent, due to the induction of TGF-beta-secreting suppressive-regulatory T cells and to local down-regulation of MCP-1 and RANTES in the spinal cord.
authors.affiliation: Department of Medical Microbiology and Immunology, Göteborg University, 413 46 Göteborg, Sweden.
authors.forename: J B
authors.initials: JB
authors.lastname: Sun
authors.forename: B G
authors.initials: BG
authors.lastname: Xiao
authors.forename: M
authors.initials: M
authors.lastname: Lindblad
authors.forename: B L
authors.initials: BL
authors.lastname: Li
authors.forename: H
authors.initials: H
authors.lastname: Link
authors.forename: C
authors.initials: C
authors.lastname: Czerkinsky
authors.forename: J
authors.initials: J
authors.lastname: Holmgren
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics; D018946:Chemokine CCL5 / Q000235:genetics; D018925:Chemokines / Q000235:genetics*; D002772:Cholera Toxin / Q000276:immunology*; D016207:Cytokines / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000517:prevention & control*; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D004676:Myelin Basic Protein / Q000276:immunology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011917:Rats, Inbred Lew; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D018932:Chemokine CCL2; D018946:Chemokine CCL5; D018925:Chemokines; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D004676:Myelin Basic Protein; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D002772:Cholera Toxin