Final Report Summary - EURO-THYMAIDE (Novel approaches to pathogenesis, diagnosis and treatment of autoimmune diseases based on new insights into thymus-dependent self-tolerance) The project was launched in Brussels on 1 January 2004 and gathered 20 academic laboratories with the highest expertise in the exploration of thymus physiology, together with 5 biotechnology small and medium-sized enterprises (SMEs). The final objective of the project was the design of innovative approaches for diagnosis and treatment of autoimmune diseases based on new knowledge of thymus-dependent self-tolerance. Type 1 diabetes (T1D) was selected as the prototype autoimmune disease to be tackled by EURO-THYMAIDE. The phenomenon of promiscuous gene expression (pGE) in the thymus was established as a cornerstone of immunological self-tolerance. The scope of pGE was more precisely delineated in medullary thymic epithelial cells (TECs) of mice, rats and humans. Genomic mapping of this gene pool showed significant genomic clustering and a high content of tissue-restricted antigens. These studies revealed high species conservation in size, composition and organization at the gene pool. Comparative analysis of pGE expression patterns at the population level and in single medullary TEC and peripheral tissues showed that the same genes are differentially regulated at both sites. Understanding of the role of AIRE in pGE was refined with respect to its cellular expression pattern, its target gene pool, its influence on T-cell deletion, antigen presentation, T-cell migration, and its molecular action. Studies on the role of pGE and central tolerance in three autoimmune diseases (T1D, myasthenia gravis and Graves' thyroiditis) uncovered common pathophysiological mechanisms, which led to a completely new paradigm. Genetic polymorphisms in the regulatory regions of target self-antigens indirectly influence the thymic transcription of these antigens by AIRE. These variations in the level of self-antigen display set threshold for self-tolerance and thus codetermine susceptibility to disease. Certain thymomas (TEC malignancies) can now be viewed as disturbed microenvironments that still sustain T-cell development but fall short of proper tolerance induction due to defects in AIRE expression, pGE and delivery of tolerogenic signals. Based on the finding that Igf2 expression is required for full tolerance to insulin, the patent 'Thymusbased tolerogenic vaccine against T1D' WO2004019965 was extended and delivered in Australia. New knowledge about the neuroendocrine control of thymus physiology was also the basis for a spin-off project supported by the Walloon Region of Belgium (ThymUp First Spin-off project). Five biotechnology bodies were involved in the project (Zentech, Apeiron Biologicals, ProImmune Ltd, Ingenium Pharmaceuticals and FIT Biotech. Two patents and one technological application (diagnostic test) were placed under commercial development. As an example of applied knowledge, the involvement of the company ProImmune Ltd (UK), a research intensive biomedical SME, gave partners the opportunity to complete the design of defined MHC multimers to detect T cells specific for autoimmune-related antigens. This application can be used to evaluate T-cell immunity in disease and in response to therapy, enabling investigators to accelerate their research and the discovery of new biopharmaceutical drugs in areas of major unmet needs, such as autoimmunity, cancer, infectious diseases and organ transplantation. Related documents Final Report - EURO-THYMAIDE (Novel approaches to pathogenesis, diagnosis and treatment of autoimmune diseases based on new insights into thymus-dependent self-tolerance)
