Inuencing the Encephalitogenic Potential of Autoreactive T Cells in a Humanized Murine Model of MS

The immunological component of MS is emphasized by the identiŽcation of several speciŽc disease-associated MHC class II alleles and the implicated involvement of myelin-speciŽc T cells in disease pathogenesis. These observations are the basis for a humanized T cell receptor (TCR)/MHC transgenic (Tg) model to study factors important for T cell encephalitogenicity and the relevance of “molecular mimics” to disease. Tg mice were created which possess the human variable components of HLA-DR4dw4 and the TCR from a clone recognizing MBP111–129, the HLA-DR4dw4-restricted immunodominant epitope of MBP. Following active and passive EAE induction, mice developed only very mild clinical symptoms despite high levels of autoreactive T cells. Studies are currently focused on factors which inuence disease development: identifying infectious mimics with increased potency (varying the antigen), and the delivery of stronger signals from the antigen-presenting cell (altering costimulation). Using positional scanning combinatorial peptide libraries and mathematical predictions to scan known microbial and human databases, we have identiŽed several peptides derived from infectious agents that stimulate the transgenic T cells with signiŽcantly higher afŽnity than MBP111–129. We are now testing the ability of these high afŽnity peptides/pathogens to alter the initiation and severity of EAE in this model. Additionally, studies using phenotypically diverse bone marrow-derived dendritic cells (DC) suggest that antigen presentation can signiŽcantly inuence the encephalitogenicity of autoreactive T cells. Immature HLADR4dw4 Tg DC activate Tg T cells to a Th0/Th1 proŽle, but cytokine-matured DC enhance a strong Th1 shift in T cells without affecting encephalitogenicity. In contrast, immature DC in the B10.PL Tg model induce Th2 T cells incapable of causing disease, yet mature DC prime T cells to become encephalitogenic. Although striking differences exist, we are now testing whether differentially primed DC may serve as promising immune therapies. Thus, this unique humanized Tg system has been a valuable tool in our characterization of several factors contributing to T cell encephalitogenicity and the consequence of molecular mimics in autoimmunity.