Oral administration of cholera toxin B subunit conjugated to myelin basic protein protects against experimental autoimmune encephalomyelitis by inducing transforming growth factor-β-secreting cells and suppressing chemokine expression

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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 Th1 cytokines IFN-γ, IL-12 and tumor necrosis factor-α, 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)-β 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-β mRNA-expressing cells was also increased, whereas there was a decrease in cells expressing Th1 or Th2 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-β-secreting suppressive-regulatory T cells and to local down-regulation of MCP-1 and RANTES in the spinal cord.

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