The intrathymic expression of insulin-related genes: implications for pathophysiology and prevention of Type 1 diabetes.

Recent experimental work has challenged and shattered the old concept of a sequestration of pancreatic islet antigens from developing T-cells within the thymic environment. There is now compelling evidence that the central immunological tolerance of the whole insulin family may be induced during the process of T-cell ontogeny in the thymus. Transcripts of insulin-like growth factor II (IGF-II), IGF-I and insulin genes have been characterized in human, rat and mouse thymuses. At the peptide level, IGF-II was shown to be the dominant polypeptide of the insulin family in the thymus from different species. Data are presented which support a dual role of thymic IGF-II both in T-cell development as well as in T-cell negative selection. Using animal models of autoimmune diabetes, current research is investigating the hypothesis that a defect of thymic T-cell education to the insulin family is implicated in the pathophysiology of human Type 1 diabetes. An efficient and secure prevention of Type 1 diabetes could be designed on the basis of the strong natural tolerogenic properties of the thymus.