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Tolerance induction by intrathymic expression of P0
Lucian Visan1, Ioana A Visan, Andreas Weishaupt
1Department of Neurology, Clinical Research Group for Multiple Sclerosis and Neuroimmunology, University of Würzburg, Würzburg, Germany.
Journal of Immunology (Baltimore, Md. : 1950)
|January 22, 2004
Summary
Genetic deficiency in myelin protein zero (P0) causes neuropathy. Gene therapy may repair this, but the repaired P0 protein could trigger autoimmunity by acting as a foreign antigen in patients.
Area of Science:
- Neuroimmunology
- Molecular genetics
- Autoimmunity
Background:
- Genetic defects in myelin protein zero (P0) cause hereditary motor sensory neuropathy.
- Gene therapy offers potential for correcting P0 deficiency, but raises concerns about immune responses to the therapeutic protein.
Purpose of the Study:
- To investigate the impact of P0 deficiency on T cell repertoire selection.
- To identify P0-specific T cell epitopes in a mouse model of P0 deficiency.
Main Methods:
- Analysis of P0 mRNA and protein expression in the thymus.
- ELISPOT assay using overlapping P0 peptides to detect T cell responses.
- Bone marrow chimera experiments to assess P0 expression and tolerance induction.
Main Results:
- P0 mRNA and protein are expressed in the thymic stroma.
- P0-deficient mice exhibit a strong T cell response to a specific P0 extracellular domain peptide (aa 41-60).
- Cryptic and subdominant P0 epitopes were identified.
- Host P0 expression is sufficient for tolerance induction, while bone marrow-derived cells contribute partially.
Conclusions:
- Genetic P0 deficiency leads to the selection of autoreactive T cells against specific P0 epitopes.
- Gene therapy for P0 deficiency may risk secondary autoimmunity due to immune responses against the corrected, previously untolerized P0 protein.