Before being able to react against infectious nonself-
antigens, the immune system has to be educated in the recognition and tolerance of neuroendocrine
proteins and this critical process takes place only in the thymus. The development of the autoimmune diabetogenic response results from a thymus dysfunction in programing central self-tolerance to pancreatic
insulin-secreting islet beta cells, leading to the breakdown of immune homeostasis with an enrichment of islet beta-cell reactive effector T cells and a deficiency of beta-cell specific natural regulatory T cells (nTregs) in the peripheral T-lymphocyte repertoire.
Insulin-like growth factor 2 (IGF-2) is the dominant member of the
insulin family expressed during fetal life by the thymic epithelium under the control of the autoimmune regulator (AIRE) gene/
protein. The very low degree of
insulin gene transcription in normal murine and human thymus explains why the
insulin protein is poorly tolerogenic as demonstrated in many studies, including the failure of all clinical trials that have attempted immune tolerance to islet beta cells via various methods of
insulin administration. On the basis of the close homology and crosstolerance between
insulin, the primary T1D
autoantigen, and
IGF-2, the dominant
self-antigen of the
insulin family, a novel type of vaccination, so-called 'negative/tolerogenic self-vaccination', is currently being developed for the prevention and cure of T1D. If this approach were found to be effective for reprograming immunological tolerance in T1D, it could pave the way for the design of other self-
vaccines against autoimmune
endocrine diseases, as well as other organ-specific
autoimmune diseases.