[Viral antigen induced autoimmunity: an animal model for diabetes mellitus type I].
To address the mechanisms of tolerance to extrathymic proteins, we have generated transgenic mice expressing the lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) in the beta islet cells of the pancreas. The fate of LCMV-GP-specific T cells was followed by breeding the GP transgenic mice with T cell receptor transgenic mice, specific for LCMV-GP and H-2Db. These studies suggest that "Peripheral tolerance" of self-reactive T cells does not involve clonal deletion, clonal anergy, or a decrease in the density of T cell receptors or accessory molecules. Instead, this model indicates that potentially self-reactive cytotoxic T cells may remain functionally unresponsive, owing to a lack of appropriate T cell activation. Infection of transgenic mice with LCMV readily abolishes peripheral unresponsiveness to the self LCMV-GP antigen, resulting in a CD8+ T cell-mediated diabetes. These data suggest that similar mechanisms may operate in several so called "T cell-mediated autoimmune diseases". A synthetic peptide corresponding to an immunodominant epitope of lymphocytic choriomeningitis virus glycoprotein (LCMV-GP) was used to prime or to tolerize CD8+ T cells in vivo, dependent on the mode of immunization. Peptide-specific tolerance was then examined in transgenic mice expressing LCMV-GP in the beta islet cells of the pancreas; these mice develop CD8+ T cell-mediated diabetes within 8-14 days after LCMV infection. Specific peptide-induced tolerance prevented autoimmune destruction of beta islet cells and diabetes in this transgenic mouse model.
Hengartner
H
H
Institut für Experimentelle Immunologie, Universität Zürich.
D000818:Animals; D000956:Antigens, Viral / Q000096:biosynthesis / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology*; D015551:Autoimmunity; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D006023:Glycoproteins / Q000096:biosynthesis / Q000276:immunology; D006183:H-2 Antigens / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology*; D008213:Lymphocyte Activation; D008217:Lymphocytic choriomeningitis virus; D051379:Mice; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000032:analysis / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000276:immunology*; D014764:Viral Proteins / Q000096:biosynthesis / Q000276:immunology
D000956:Antigens, Viral; D006023:Glycoproteins; D006183:H-2 Antigens; D011948:Receptors, Antigen, T-Cell; D014764:Viral Proteins