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A targeted DNA vaccine encoding Fas ligand defines its dual role in the regulation of experimental autoimmune encephalomyelitis
Gizi Wildbaum, … , Gila Maor, Nathan Karin
Gizi Wildbaum, … , Gila Maor, Nathan Karin
Published September 1, 2000
Citation Information: J Clin Invest. 2000;106(5):671-679. https://doi.org/10.1172/JCI8759.
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A targeted DNA vaccine encoding Fas ligand defines its dual role in the regulation of experimental autoimmune encephalomyelitis

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Abstract

This study used naked DNA vaccination to induce breakdown of tolerance to self and thus elicit immunological memory to native, membrane-bound Fas ligand (FasL). Upon induction of experimental autoimmune encephalomyelitis (EAE), this memory was turned on to provide protective immunity. FasL-specific autoantibodies isolated from protected animals differentially downregulated the in vitro production of TNF-α, but not IFN-γ, by cultured T cells. These autoantibodies were highly protective when they were administered to rats at the onset of EAE. In contrast, administration of these FasL-specific Ab’s to EAE rats after the peak of the acute phase of disease prevented spontaneous recovery from disease. This extended illness is partially explained by inhibition of mononuclear cell apoptosis at the target organ, which resulted in increased accumulation of T cells and macrophages at the site of inflammation. Hence, FasL exerts two distinct, stage-specific regulatory functions in the control of this T-cell mediated autoimmune disease of the central nervous system.

Authors

Gizi Wildbaum, Juergen Westermann, Gila Maor, Nathan Karin

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Figure 3

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FasL-specific Ab’s generated in DNA-vaccinated rats significantly reduce...
FasL-specific Ab’s generated in DNA-vaccinated rats significantly reduce TNF-α production during antigen-specific primary response. Spleen cells from p68-86/CFA-primed (day 9) Lewis rats were cultured with or without the addition of 100 μM of MBP p68-86. Cultured cells received 100 ng/mL of FasL-specific Ab’s (IgG from serum of FasL DNA–vaccinated EAE rats [Figure 1, day 13] purified on FasL CNBr–activated Sepharose column) or control IgG from naive rats, as indicated. After 72 hours of stimulation, TNF-α (a), IFN-γ (b), and IL-4 (c) were determined. The effect of these Ab’s on the primary T-cell response to 100 μM of MBP p68-86 (d) was determined by an in vitro proliferation assay. Antigen specificity of these Ab’s (e) was determined by a direct ELISA assay. The recombinant Fas ligand, which we produced, or commercially available TNF-α was coated onto 96-well ELISA plates at concentrations of 50 ng/well. Rat anti-sera, in serial dilutions from 28 to 230, were added to ELISA plates. Goat anti-rat IgG alkaline phosphatase-conjugated Ab’s were used as a labeled Ab and p-NPP was used as a soluble alkaline phosphatase substrate. Results are shown as mean of triplicates ± SE. AP < 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 5 patents
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