Breaking and restoring immune tolerance to pancreatic beta-cells in type 1 diabetes

Abstract

Purpose of review Type 1 diabetes (T1D) results from the loss of immune tolerance to pancreatic beta-cells leading to their destruction. Immune intervention therapies tested in T1D so far delayed progression but failed to restore tolerance, which partly explains their lack of durable clinical efficacy. Recent findings The role of beta-cells and islets themselves in dialogue with their micro- and macro-environment including the immune system and the intestinal microbiome is increasingly evident. Indeed, islets can both maintain and break immune tolerance. Some recent immune therapies in cancer that block immune regulation also break tolerance. Induction of immune tolerance requires activating immune activation too, whereas immune suppression precludes this process. Immunotherapy alone my not suffice without engaging islets to restore tolerance and preserve beta-cell function. Summary New insight into the role of islet tissue and its interaction with its environment in preserving or breaking tolerance has contributed to understand the development of islet autoimmunity and T1D. Knowing which factors in islets and the immune system contribute to maintaining, breaking, and restoring the balance in the immune system is critical to prevent initiation and reverse disease progression, and guides the design of novel tolerogenic strategies for durable therapeutic intervention and remission that target both the immune system and distressed islets.

From Disease and Patient Heterogeneity to Precision Medicine in Type 1 Diabetes

“…Also, gut bacteria stimulate IL-10 production and maternal antibiotics intake in non-obese diabetic (NOD) mice increases the risk of diabetes development in new-borns whereas low intrauterine gluten exposure and vitamin D3 supplements in human infants decrease the risk to develop T1D ( 39 , 40 ). This further supports the idea that dysbiosis contributes to early T1D development ( 41 – 44 ). Curiously, fecal microbiome transplantation showed promise halting disease progression in newly diagnosed T1D patients ( 45 ).…”

Advanced Glycation End Products and Inflammation in Type 1 Diabetes Development

“…Normally, when this occurs, antigen-specific cells recognizing “self”-antigens are usually deleted, neutralized or suppressed by processes such as secondary selection in the peripheral tissues, including at sites such as the local lymph nodes and spleen [ 23 ]. However, in individuals with T1D, there is a loss of tolerance to self-antigens due to defects in central and peripheral tolerance, which is elegantly reviewed here [ 21 , 24 ]. The reasons for this are not well understood.…”

Immune Editing: Overcoming Immune Barriers in Stem Cell Transplantation

“…Overcoming barriers to successful engraftment can have a huge impact on the costs of a cell therapy. For example, excessive cell death due to activation of stress pathways during transplantation of pancreatic β cells impedes their clinical translation [95]. Interfering with those stress pathways could potentially improve cell survival during and post transplantation when a great number of cells are lost due to stress-induced cell death.…”

“…Interfering with those stress pathways could potentially improve cell survival during and post transplantation when a great number of cells are lost due to stress-induced cell death. Cell death can also expose NA that may result in an exacerbated immune attack [95]. For pancreatic β cells, it has been established that an upregulation of HLA class I in T1D patients is correlated with increased CD8+ T cell infiltration [96].…”