When activated inappropriately, T cells are responsible for the development of autoimmune diseases, including autoimmune diabetes. Currently, the only curative treatment of overt diabetes consists of pancreatic islets or whole pancreas transplantation. However, T cell-mediated allograft rejection and consequent requirement for life-long immunosuppression with its complications of infections and tumor development is the major limitation to this treatment. Understanding the complexities of how T cells become activated in vivo to reject allogeneic grafts may lead to new immunosuppressive regimens with the capacity to induce graft-specific tolerance. The biochemical signaling pathways necessary in T cells for promoting acute allograft rejection in vivo are not well understood. T cell activation following TCR ligation and CD28 costimulation in vitro results in activation of multiple signaling cascades leading to the nuclear translocation of several transcription factors including nuclear factor of activated T cells (NFAT), activating protein 1 (AP-1) and nuclear factor-B (NFB). Whether activation of these transcription factors is necessary in vivo for acute allograft rejection is not known. Of these transcription factors, NF-B is a lead candidate for contributing to acute rejection, as its activation has been linked to cell survival, differentiation, and cytokine production in different cell systems. Dr. Alegre’s transplantation studies investigate whether T cell-intrinsic NF-B activation in vivo is required for acute rejection of allogeneic grafts.

To this end, Dr. Alegre has developed a model of pancreatic islet transplantation, as well as models of cardiac and skin transplantation. She has obtained mice with impaired NF-B activation in T cells, either because of transgenic expression of a non degradable form of the inhibitor IB, or following gene targeting of 2 NF-B subunits, p50 and p52, essential for DNA binding activity. Bone marrow from the latter mice can be used to populate RAG-deficient mice with NF-B-deficient lymphoid cells, and resulting chimeric animals will be utilized as recipients. Preliminary data indicate that mice with impaired NF-B activation in T cells are tolerant to cardiac and pancreatic islets but not to skin allografts. Further experiments are underway to address the mechanisms leading to tolerance and rejection, respectively. The contribution of direct versus indirect antigen presentation, of the number and type of donor APCs in the graft and of the anatomical location of the grafts will be examined.