While EAE has been an invaluable model for the immunopathogenesis of multiple sclerosis, it has sometimes been difficult to bridge the gap between findings and therapies in the rodent models and the cellular and molecular interactions that can be studied in the human disease. Humanized transgenic models offer a means of achieving this, through the expression of disease-implicated HLA class II molecules, co-expressed with a cognate HLA-class II-restricted, myelin-specific TCR derived from a human T cell clone implicated in disease. We have generated such a transgenic line, called line 8, that co-expresses a high level of HLA-DR15 and a human TCR specific for HLA-DR15/MBP 85-99. T cells from the transgenic line are skewed to the CD4 single-positive compartment and produce IFN-gamma in response to peptide from mylein basic protein. Mice develop a spontaneous disease phenotype, showing poverty of movement, although this rarely develops into paralysis except following immunization with peptide. On induction of paralysis by immunization with peptide, disease correlates with epitope spread to a number of additional, HLA-DR15-restricted myelin epitopes. This model should be valuable for analyzing epitope spread in a humanized immunogenetic environment and for the testing of specific immunotherapies.