Thymic self-antigens for the design of a negative/tolerogenic self-vaccination against type 1 diabetes

Abstract

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 b cells, leading to the breakdown of immune homeostasis with an enrichment of islet b-cell reactive effector T cells and a deficiency of b-cell specific natural regulatory T cells (nTregs) in the peripheral Tlymphocyte 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 b 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 selfvaccination', 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 organspecific autoimmune diseases. ''Autoimmune disease can be a depressing subject. In Shakespearian terms, 'it is a tale told by an idiot. . .signifying nothing'. In more modern metaphor, it is an error made at random in an enormous, delicately programmed computer. Nature has no other way of handling genetic error than by eliminating the faulty, and the physician handling autoimmune diseases can expect no help from her.'' Sir F. MacFarlane Burnet, 1972 IntroductionIn 1965, our late Belgian colleague Willy Gepts observed inflammatory infiltrates of mononuclear cells invading Langerhans' islets in the pancreas of deceased young diabetic patients [1]. In a prophetical analysis, he discussed his innovative results with the following words: 'It seems probable that, in the pancreas of acute diabetics, we had the opportunity to catch the final stages of a process which has been going on for an indefinite time, perhaps from birth on'. Since this pioneering work, research conducted worldwide has firmly established that type 1 diabetes (T1D) -previously called juvenile diabetes, and insulin-dependent diabetes -is the final result of a highly selective autoimmune response that generates an inflammation (insulitis), followed by the death of insulin-secreting islet b cells in the pancreas. Incidence of T1D peaks around 10-14 years and this disease affects AE20 million people worldwide (approximately 10%...

Persistent Infection of Thymic Epithelial Cells with Coxsackievirus B4 Results in Decreased Expression of Type 2 Insulin-Like Growth Factor

“…Ins2 was not expressed by MTE cells or was expressed at a very low level below the detection threshold of our RT-qPCR. The latter observation is not so surprising, since a very low degree of insulin gene transcription in healthy murine and human thymus had already been described and correlated to the poor tolerogenicity of insulin protein evidenced in many studies (20). In contrast, Igf1 transcripts were detectable, and a decreased level of these transcripts was observed in CV-B4 E2-infected MTE cultures as well, but to a lesser extent than Igf2 transcripts.…”

“…Indeed, administration of IGF-2-derived self-antigens (B11-25 sequence) to peripheral blood mononuclear cells from DQ8 ϩ type 1 diabetic patients seems to be an efficient approach in T1D prevention, since it elicits a tolerogenic/regulatory cytokine profile (interleukin-10 [IL-10], IL-10/ gamma interferon [IFN-␥], and IL-4) statistically different from the one induced by Ins B9-23 (19). This issue is currently investigated by vaccination of NOD mice with recombinant human IGF-2 alone or in combination with adjuvants (20). The association between CV-B4 infection and the loss of immune self-tolerance is still unclear.…”

“…Besides, Igf2 could be employed both in the reprogramming of immunological tolerance to islet ␤ cells and in the regeneration of a functional ␤-cell mass (20). On the basis of the close homology and cross-tolerance between insulin and IGF-2, a novel type of negative/tolerogenic self-vaccination is currently developed for prevention and cure of T1D (23).…”

Programming of neuroendocrine self in the thymus and its defect in the development of neuroendocrine autoimmunity

“…We proposed that IGF-2 could be a safer and more valuable basis for developing a specific “negative/tolerogenic self-vaccination,” on the basis that Igf2 transcription is defective in the thymus of BBDP rats (Kecha-Kamoun et al, 2001) and that IGF-2 mediates significant cross-tolerance to insulin (Hansenne et al, 2006). The concept of negative self-vaccination implies both the competition between IGF-2 and insulin-derived epitopes for presentation by DQ2 and DQ8 alleles, as well as a tolerogenic response—including recruitment of Treg cells–induced by MHC-presentation of IGF-2 self-peptides (Geenen et al, 2004, 2010). …”

The Role of the Thymus in the Integrated Evolution of the Recombinase-Dependent Adaptive Immune Response and the Neuroendocrine System

“…According to the novel knowledge gained in type 1 diabetes pathogenesis and the central role of a thymus dysfunction in its development, the control of the autoimmune process could be obtained by (re)programming ␤ -cells through the potent tolerogenic properties of the thymus, in particular the repertoire of thymic type 1 diabetes-related self-antigens. Contrary to insulin, the 'altered self IGF-2', IGF-2 and derived epitopes might be a much more appropriate choice for a novel type of negative self-vaccination that associates competition for major histocompatibility complex presentation and regulatory responses downstream, as well as potential bystander suppression of autoimmune responses to other type 1 diabetes-related autoantigens [41] . This hypothesis is currently being investigated by vaccination of NOD mice with recombinant human IGF-2 alone or in combination with tolerogenic adjuvants.…”