One of the goals of this project is to examine mechanisms of activation of autoreactive T lymphocytes in the animal model for multiple sclerosis (MS), i.e. experimental allergic encephalomyelitis (EAE). EAE is induced in susceptible animals either by injection of myelin proteins or peptides or via adoptive transfer of myelin-specific T cells from EAE animals into naive animals. Many important aspects of the pathogenesis and treatment of demyelinating diseases such as MS have been studied in the EAE model. With respect to an early event in disease pathogenesis, i.e. the activation of autoreactive T cells, it has been shown that viruses and bacteria can lead to the activation and expansion of autoreactive T cells via molecular mimicry or antigenic similarity between foreign agent and autoantigen. In order to study these questions, we have chosen to develop humanized transgenic mice that express chimeric receptors combining transmembrane regions of mouse class II with the antigen-binding domain of the MS-associated HLA-DR alleles DRB1*1501 and DRB1*0401, and on the T cell receptor (TCR) side, the TCR constant region from the mouse with the antigen-specific domains from human MBP-specific TCRs. Three double transgenic mouse lines have been generated: Designation: DR restriction Specificity MS2-3C8 DRB1*0401 MBP (111-129); 1113-1C2 DRB1*0401 MBP (111-129); TL 3A6 DRB5*0101 MBP (83-99). These animals are now available. In contrast to the two other double transgenic, humanized MBP-specific mice that have been described in the literature, MS2-3C8 and 1113-1C2 do not develop spontaneous disease, but only if TCR transgenic T cells are transferred into irradiated host mice or those with recombinase knockout (Rag-). The antigen specificity, positive and negative selection in these animals may be the reason for those differences. The TL3A6 mice will be tested for EAE development shortly. These animals will be very valuable for molecular mimicry studies and for testing antigen-specific treatment approaches before they are tested in MS patients. These experiments are currently ongoing. As a first very interesting result, the MS2-3C8 transgenic mouse shows a different phenotype than conventional EAE models, i.e. the animals develop cranial nerve deficits, ataxia, swallowing problems. These findings indicate that the antigen-specificity of autoreactive TCR is in para a determining factor for the clinical disease phenotype. A second project examines the tolerizing capacity of antigen-pulsed dendritic cells in EAE. A further experimental series address the migration and differentiative capacity of various neural and glial progenitor cells including embronic stem cells into the brain in EAE animals. These studies aim at developing myelin repair strategies in EAE, MS. Finally, a model for a chronic bacterial infection of the CNS is currently being studied in order to understand better the molecular events involved in the development of chronic central nervous system Lyme disease. This project is being pursued in collaboration with the National Institute of Allergy and Infectious Diseases. Publications about the humanized transgenic mice and the tolerizing capacity of dendritic cells have been submitted.
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