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

Abstract

Type 1 diabetes (T1D) remains a devastating disease that requires much effort to control. Life-long daily insulin injections or an insulin pump are required to avoid severe complications. With many factors contributing to disease onset, T1D is a complex disease to cure. In this review, the risk factors, pathophysiology and defect pathways are discussed. Results from (pre)clinical studies are highlighted that explore restoration of insulin production and reduction of autoimmunity. It has become clear that treatment responsiveness depends on certain pathophysiological or genetic characteristics that differ between patients. For instance, age at disease manifestation associated with efficacy of immune intervention therapies, such as depleting islet-specific effector T cells or memory B cells and increasing immune regulation. The new challenge is to determine in whom to apply which intervention strategy. Within patients with high rates of insulitis in early T1D onset, therapy depleting T cells or targeting B lymphocytes may have a benefit, whereas slow progressing T1D in adults may be better served with more sophisticated, precise and specific disease modifying therapies. Genetic barcoding and immune profiling may help determining from which new T1D endotypes patients suffer. Furthermore, progressed T1D needs replenishment of insulin production besides autoimmunity reversal, as too many beta cells are already lost or defect. Recurrent islet autoimmunity and allograft rejection or necrosis seem to be the most challenging obstacles. Since beta cells are highly immunogenic under stress, treatment might be more effective with stress reducing agents such as glucagon-like peptide 1 (GLP-1) analogs. Moreover, genetic editing by CRISPR-Cas9 allows to create hypoimmunogenic beta cells with modified human leukocyte antigen (HLA) expression that secrete immune regulating molecules. Given the differences in T1D between patients, stratification of endotypes in clinical trials seems essential for precision medicines and clinical decision making.

Keywords: autoimmune disease (AD); disease endotypes; disease heterogeneity; genetic risk score; immune intervention therapy; islet autoimmunity; type 1 diabetes immunopathogenesis.

Figure 1

Pathophysiology and endotypes of type 1 diabetes (T1D). Both beta-cells and the immune system can provoke and diminish autoimmunity and beta-cell destruction. The contribution of the major cell types in disease progression differs depending on the age of disease onset. Green indicates a protective role and red points to a progressive role toward T1D development. The immune imbalance is greatest in patients developing T1D at younger ages, where the pathology is more acute and severe. With age, the degree of autoimmunity and the rate of beta-cell loss declines. CD4 T cells are activated by islet autoantigens that vary between disease endotypes. IL-2 differentially stimulates CD8+ effector T-cells as well regulatory T cells (low dose IL-2). Tregs protect against beta cell destruction. IL-6 stimulates inflammation and inhibits regulation. Activated CD8 T cells are triggered by IFN-alpha and IL-1 to attack beta cells. Due to stress, beta cells overexpress HLA Class 1 (HLA 1) and secrete IFN-alpha that provoke and attract CD8 cells. This destructive process may be inhibited by stress-reducing proteins GLP-1 and EGF. IFN-γ signaling stimulates PD-L1 expression and beta cell survival. This figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

Figure 2

Innovative technologies and solutions. Promising strategies are shown that target autoimmunity (red), insulin deficiency (blue) or both (purple). Autoimmunity solutions: (1) Long-term and low-level antigen expression by AAV infection; (2) Combination therapy of effector T cell depletion followed by regulatory T cell stimulation; (3) Selective CD25-agonist/CD-122 antagonist. Insulin solutions: (1) Glucose sensing beta-cell like organoids that secrete sustained insulin by ex vivo WNT and IFN-γ signaling; (2) Humanized pancreas growth by patient-derived stem cell injection into pig blastocyst; (3) Hydrogels and TMTD-alginate microspheres to avoid rejection and necrosis. Solutions for both: (1) Trial stratification and treatment choice based on endotype; (2) Engineering hypoimmunogenic beta cells using CRISPR-Cas9; (3) Beta cell stress reducers to lower inflammation and increase beta cell function.