Optimal Tolerogenic Dendritic Cells in Type 1 Diabetes (T1D) Therapy: What Can We Learn From Non-obese Diabetic (NOD) Mouse Models?

Abstract

Tolerogenic dendritic cells (tolDCs) are explored as a promising standalone or combination therapy in type 1 diabetes (T1D). The therapeutic application of tolDCs, including in human trials, has been tested also in other autoimmune diseases, however, T1D displays some unique features. In addition, unlike in several disease-induced animal models of autoimmune diseases, the prevalent animal model for T1D, the NOD mouse, develops diabetes spontaneously. This review compares evidence of various tolDCs approaches obtained from animal (mainly NOD) models of T1D with a focus on parameters of this cell-based therapy such as protocols of tolDC preparation, antigen-specific vs . unspecific approaches, doses of tolDCs and/or autoantigens, application schemes, application routes, the migration of tolDCs as well as their preventive, early pre-onset intervention or curative effects. This review also discusses perspectives of tolDC therapy and areas of preclinical research that are in need of better clarification in animal models in a quest for effective and optimal tolDC therapies of T1D in humans.

Role of the PD-1/PD-L1 Dyad in the Maintenance of Pancreatic Immune Tolerance for Prevention of Type 1 Diabetes

“…Considering the important role of the PD-1/PD-L1 pathway in controlling β cell autoimmunity and in maintaining immune homeostasis in pancreatic tissues is possible to envision several therapeutic approaches that target this inhibitory pathway for T1D prevention and/or treatment ( Figure 2 ). In particular, Adoptive cell therapy (ACT) with tolerogenic dendritic cells (DCs) and Tregs is explored as a promising standalone or combination therapy to counter-regulate β cell autoimmunity in T1D ( 95 ). At this moment, there is one completed ( 96 ) and one ongoing phase I clinical trial led by Dr. Roep with autologous tolerogenic DCs in patients with new onset T1D (CT No: NTR5542).…”

“…At this moment, there is one completed ( 96 ) and one ongoing phase I clinical trial led by Dr. Roep with autologous tolerogenic DCs in patients with new onset T1D (CT No: NTR5542). Over the years, several protocols of tolerogenic DCs have been developed, with and without in vitro supplied antigen [reviewed here ( 95 )]. Tolerogenic DCs are thought to act via Treg expansion and induction, T-cell deletion, T-cell anergy and hyporesponsiveness.…”

Immunomodulation for optimal cardiac regeneration: insights from comparative analyses

“…Current regenerative therapies fail to address the issue of autoreactivity, meaning that tissue destruction is likely to continue, despite intervention 12 . Dendritic cells (DCs) have recently been identified as a population with potential to modulate the process of postinfarction repair and could be engineered to skew cardiac populations, such as macrophages and T cells, towards tolerance post-MI, a technique utilised in rheumatoid arthritis 96 and type-1 diabetes 97 . Tolerogenic DCs, treated with TNF-α and cardiac lysate, were injected into post-injury adult mice, incapable of intrinsic regeneration.…”

Autoantigen Treatment in Type 1 Diabetes: Unsolved Questions on How to Select Autoantigen and Administration Route

“…Tregs should be able to inactivate the self-reactive T cells in the periphery that have escaped intra-thymic negative selection. Autoantigen treatment might lead to immune modulation through the development of tolerance against certain autoantigens and by influencing the development of tolerogenic dendritic cells [38].…”