Abstract Details

Title Anti-VLA4-Mediated Inhibition of Humeral Autoimmunity in EAE: Dependence on Epithelial V-Like Antigen Expression

Topic MS and Related Diseases

Presentation(s) P05 - (-)

Poster/Presentation
Number 165

Objective

Background BACKGROUND: Natalizumab inhibits the transmigration of activated T lymphocytes into the brain and is highly efficacious in multiple sclerosis (MS). However, from a pharmacogenomic perspective, its efficacy and safety in specific patients remain unclear.

Design/Methods DESIGN/METHODS: Here we analyzed the therapeutic effect of anti-VLA4 treatment on experimental autoimmune encephalomyelitis (EAE) in mice that lack expression of EVA. This molecule has been previously characterized in human lymphocytes and animal models, and it is expressed in activated immune cells and at the blood-cerebrospinal fluid barrier. EVA-knockout mice demonstrate normal development and lifespan.

Results RESULTS: Following active induction of EAE using MOG35-55, these mice developed more severe EAE and white matter tissue injury as compared to wild type controls. This severe EAE phenotype did not respond to anti-VLA4 treatment. In both the control antibody and anti-VLA4 conditions, these mice demonstrated enhanced serum autoantibody levels, CNS invasion of mature B lymphocyte (CD19+, CD21+, sIgG+), and extensive complement deposition within lesions. Wild type mice treated with control antibody also demonstrated CNS invasion of CD19+CD21+sIgG+ cells and serum autoantibody. In contrast, wild type mice treated with anti-VLA4 demonstrated reduced serum autoantibody levels as compared to wild type controls and EVA-knockout mice. As expected, anti-VLA4 treatment in wild type mice reduced the total numbers of all CNS mononuclear cells, markedly decreased CD4 T lymphocyte invasion, and also reduced the frequency of CD19+CD21+sIgG+ cells in the CNS.

Conclusions CONCLUSIONS: These results suggest that anti-VLA4 treatment can reduce B lymphocyte-mediated autoimmunity in some individuals and that EVA expression is necessary for an optimal therapeutic response. We postulate that these findings could optimize the selection of treatment responders.

Authors/Disclosures
Michael Carrithers, MD, PhD (University of Illinois College of Medicine) PRESENTER	The institution of Dr. Carrithers has received research support from Biogen.
	No disclosure on file
	No disclosure on file
Nicholas E. Hallworth, PhD (Biogen)	No disclosure on file
Stefan Lanker, PhD	No disclosure on file
Sami Fam	Sami Fam has received personal compensation for serving as an employee of Alexion Pharmaceuticals. Sami Fam has or had stock in Astra Zeneca.

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