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A role for surface lymphotoxin in experimental autoimmune encephalomyelitis independent of LIGHT
Jennifer L. Gommerman, … , Cheryl Nickerson-Nutter, Jeffrey L. Browning
Jennifer L. Gommerman, … , Cheryl Nickerson-Nutter, Jeffrey L. Browning
Published September 1, 2003
Citation Information: J Clin Invest. 2003;112(5):755-767. https://doi.org/10.1172/JCI18648.
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Article Autoimmunity

A role for surface lymphotoxin in experimental autoimmune encephalomyelitis independent of LIGHT

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Abstract

In studies using genetically deficient mice, a role for the lymphotoxin (LT) system in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) has remained controversial. Here, we have reassessed this conclusion by using a fusion protein decoy that blocks the LT pathway in vivo without evoking the developmental defects inherent in LT-deficient mice. We have found that inhibition of the LT pathway prevented disease in two models of EAE that do not rely on the administration of pertussis toxin. Surprisingly, disease attenuation was due to specific blockade of LTαβ binding rather than the binding of LIGHT to its receptors. In a third system that requires pertussis toxin, LT inhibition did not affect disease, as was observed when the same model was used with LT-deficient mice. Disease prevention in pertussis toxin–free models was associated with defects in T cell responses and migration. When the DO11.10 T cell transgenic system was used, inhibition of the LT pathway was shown to uncouple T cell priming from T cell recall responses. Therefore, it is hypothesized that the LT pathway and its ability to maintain lymphoid microenvironments is critical for sustaining late-phase T cell responses in multiple sclerosis.

Authors

Jennifer L. Gommerman, Keith Giza, Stuart Perper, Irene Sizing, Apinya Ngam-ek, Cheryl Nickerson-Nutter, Jeffrey L. Browning

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Figure 1

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Disease is prevented by LTβR-Ig or anti-LTβ treatment in an acute rat EA...
Disease is prevented by LTβR-Ig or anti-LTβ treatment in an acute rat EAE model. (a) Lewis rats were treated with either control human IgG (diamonds), LTβR-Ig (circles), or N297Q LTβR-Ig (squares) 1 day prior to immunization with MBP-peptide in CFA, and disease was scored by measuring tail and limb paralysis. (b) Dose response to LTβR-Ig was evaluated in the rat EAE model by administering LTβR-Ig at the indicated dose. The percentage of inhibition of disease was calculated by determining the decrease in clinical score on the peak day of disease. (c) Lewis rats were treated with either control huIgG (diamonds), HVEM-Ig (squares), anti-murine LTβ (open circles), or control mAb HA4/8 (filled circles) 1 day prior to immunization with MBP-peptide in CFA. Treatment with anti-LTβ and HA4/8 was continued on days 3, 5, and 7 after immunization. Eight animals were used for each group, and the experiment was performed three times with similar results. Experiments using anti-LTβ, HVEM-Ig, and HA4/8 were performed two times with similar results.
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