One of the central issues in immunology concerns the way in which the immune system is able to discriminate between self and non-self molecules, so that an immune response may be mounted to foreign pathogens while the body's own constituents are tolerated. However, this ability is impaired in some patients and results in auto-immune diseases in which the patients' own tissues are damaged by their immune system. A better understanding of the mechanisms of the tolerance is required to further the basic knowledge of the immune system and to develop insights into how tolerogenic mechanisms break down, leading to a variety of autoimmune conditions. This knowledge may lead to new methods of therapy and prevention of these diseases. The most important cell type upon which tolerance must be imposed is the T lymphocyte which matures in the thymus. Recently, the way in which T cells become tolerant to the antigens present in the thymus has been characterized, but it is not clear how responses to extra-thymic molecules are avoided. Therefore, the primary aim of this proposal is to investigate the mechanisms by which tolerance to self molecules not expressed in the thymus is imposed and maintained. In order to investigate these processes, transgenic mouse models will be used which produce in defined extrathymic sites the class I histocompatibility antigen, H-2Kb. These mice exhibit tolerance in vivo but not in vitro to H-2Kb and present a unique model for investigating tolerance induction. Other transgenic mice will be obtained whose T cells express only H-2Kb receptors, or which produce interleukin-2 in pancreatic Beta cells. The activity, phenotype and date of H-2Kb-reactive T cells will be determined in each of these transgenic mice. The methods required for this work (including production and characterization of transgenic mice, in vitro and in vivo assays of T cell function, skin and thymus grafts, proliferation assays, adult and neonatal thymectomy) have all been successfully used by the applicants.
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