Oral Presentation The 13th International Congress of the Immunology of Diabetes Society 2013

HLA-transgenic Mouse Models for Biomarker and Immune Tolerance Investigations (#41)

Teresa DiLorenzo 1
  1. Albert Einstein College of Medicine, Bronx, NY, United States

CD8 T cells specific for islet antigens are present in the blood and islets of type 1 diabetes patients and are required for disease development in NOD mice. Identification of CD8 T cell epitopes allows tools to be developed for immune monitoring and antigen-specific interventions. The NOD mouse continues to yield a wealth of information that sheds light on the pathogenesis of the human disease. This is especially true in the case of the antigenic targets of CD8 T cells. HLA-transgenic NOD mice have proven particularly valuable in facilitating the identification of epitopes that are important in the human disease, as the peptides recognized can be more readily translated to patients (provided they are well-conserved between the mouse and human antigens). This has proven to be the case for epitopes we have identified using mice transgenic for HLA-A*0201 or A*1101. This success prompted us to expand this work, and new models are being characterized, including mice expressing HLA-B*3906, a type 1 diabetes susceptibility allele that is associated with reduced age at onset. Each of the HLA molecules under study is representative of a different HLA supertype. This approach increases the population coverage of antigen-based tests and therapeutics arising from our epitope identification efforts. We are also incorporating other human susceptibility factors (e.g., reduced thymic insulin expression) and human antigens into our models. The development of models incorporating human T cells has been hampered by the lack of a ready supply of human islet-specific T cells. We have recently overcome this problem by transducing human T cells with lentiviral vectors encoding human T cell receptors specific for a beta cell antigen. This has allowed us to engineer human islet-specific T cells at will, an advance that should lead to improved models for the testing of immune tolerance approaches.