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Advances in Immunotherapeutic Approaches to Type 1 Diabetes
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Advances in Immunotherapeutic Approaches to Type 1 Diabetes

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (31 January 2020) | Viewed by 39237

Special Issue Editor

Dr. Alessandra Fierabracci

E-Mail Website
Guest Editor
Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
Interests: autoimmunity; type 1 diabetes; endocrinopathies; T regulatory cells; autoreactive T cells; nanotechnologies; NK cells; extracellular vesicles; immunoregulation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Type 1 diabetes (T1D) is an organ-specific autoimmune endocrinopathy, where autoreactive T lymphocytes destroy target islet β cells producing insulin. T1D is the third most common metabolic disorder in the world after obesity and thyroid disorders. Epidemiological studies estimate that the prevalence of diabetes has increased over the past 30–40 years worldwide. Clinically, T1D presents with interrelated metabolic, vascular, and neuropathic sequelae, and, after the onset of the disease, if it is not promptly treated with insulin, severe clinical manifestations can occur such as ketoacidosis, potential coma, and death. Nevertheless, substitutive administration in multiple daily injections of insulin will never reproduce the molecule physiological circadian rhythm. The treatment always allows the patient to escape certain death but does not treat the ongoing autoimmune process. A significant advance beyond the state of art is therefore the effect that any immunotherapeutic intervention may play in halting pathogenic immunological mechanisms, thereby preserving the residual hormone producing cells. This would improve metabolic stability during the disease course in order to avoid the typical ‘instability’ that requires adjustments to daily insulin administration and continuous glucose monitoring, thereby preventing or reducing long-term complications.

This Special Issue focuses on several immunotherapeutic approaches being experimented with in T1D.

Dr. Alessandra Fierabracci
Guest Editor

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Keywords

  • autoimmunity
  • Type 1 Diabetes
  • T regulatory cells
  • autoreactive T cells
  • dendritic cells
  • nanotechnologies
  • NK cells
  • extracellular vesicles
  • cytokines
  • antigen-specific therapies
  • anti-inflammatory therapies
  • immunoregulation

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Related Special Issue

Published Papers (7 papers)

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Research

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6 pages, 355 KiB  
Communication
A Novel Quantitative Approach to Staging and Assessing Recovery from Type 1 Diabetes Mellitus: The Type 1 Diabetes Mellitus Metabolic Recovery Index
by Tihamer Orban, Nara T. Orban, Heyam Jalahej and Piers E. F. Daubeney
Int. J. Mol. Sci. 2020, 21(3), 992; https://doi.org/10.3390/ijms21030992 - 3 Feb 2020
Cited by 1 | Viewed by 2885
Abstract
Discovery of insulin in 1921 changed the lives of patients with type 1 diabetes (T1DM) forever. What had been a death sentence became a manageable, albeit chronic, disease. Insulin did not cure the disease, as it did not address the actual disease process, [...] Read more.
Discovery of insulin in 1921 changed the lives of patients with type 1 diabetes (T1DM) forever. What had been a death sentence became a manageable, albeit chronic, disease. Insulin did not cure the disease, as it did not address the actual disease process, but instead treated its sequelae, namely elevated blood sugars. Importantly, insulin administration fails to ensure normoglycaemia. Even with the most sophisticated ‘near closed-loop’ methods, glucose homeostasis is not restored to normal. T1DM patients face complications, both short-term, such as hypo- and hyperglycaemia, and long-term, with increased glycosylation of proteins leading to eye, kidney, nervous system and other sequelae. These complications are associated with significant morbidity and mortality even after intensive insulin treatment. Nearly 100 years after the discovery of insulin, we continue to face the challenge of addressing the disease process itself, in order to fundamentally improve the life of these patients. There are major efforts to achieve just that: to completely arrest the autoimmune process destroying the insulin-producing cells in the pancreas, or at least significantly slow the process to blunt and delay short- and long-term complications. The aim of this Communication is to propose a novel assessment tool that would serve as a quantitative outcome measure by which therapies, short of clinical cure, may be compared and their true benefit to the treatment of diabetes assessed. Full article
(This article belongs to the Special Issue Advances in Immunotherapeutic Approaches to Type 1 Diabetes)
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14 pages, 2200 KiB  
Article
A Phase II, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study Evaluating the Efficacy and Safety of Alpha-1 Antitrypsin (AAT) (Glassia®) in the Treatment of Recent-Onset Type 1 Diabetes
by Yael Lebenthal, Avivit Brener, Eli Hershkovitz, Naim Shehadeh, Shlomit Shalitin, Eli C. Lewis, Dana Elias, Alon Haim, Galia Barash, Neta Loewenthal, Nehama Zuckerman-Levin, Michal Stein, Naveh Tov and Marianna Rachmiel
Int. J. Mol. Sci. 2019, 20(23), 6032; https://doi.org/10.3390/ijms20236032 - 29 Nov 2019
Cited by 16 | Viewed by 3425
Abstract
Our aim was to assess the efficacy, safety, and tolerability of alpha-1 antitrypsin (AAT) as a therapeutic modality for β-cell preservation in patients with recent-onset type 1 diabetes. Seventy type 1 diabetes patients (37 males; mean age 13.1 ± 4.1years) were randomized to [...] Read more.
Our aim was to assess the efficacy, safety, and tolerability of alpha-1 antitrypsin (AAT) as a therapeutic modality for β-cell preservation in patients with recent-onset type 1 diabetes. Seventy type 1 diabetes patients (37 males; mean age 13.1 ± 4.1years) were randomized to treatment with 22 infusions of AAT (Glassia®) (60 or 120 mg/kg) or placebo. The primary outcome was the area under the curve (AUC) of C-peptide from a 2-h mixed-meal tolerance test after 52 weeks. At week 52, C-peptide was 0.9, 0.45, and 0.48 pmol/mL in the AAT-120, AAT-60, and placebo groups (p = 0.170 and p = 0.866 vs. placebo, respectively). The declines in C-peptide glycated hemoglobin (HbA1c) and the total insulin dose (U/kg) were similar across groups. Within the predefined 12–18-years subgroup, the C-peptide AUC decreased significantly in the placebo and AAT-60 groups (−0.34 and −0.54 pmol/mL, respectively, p < 0.01), with a borderline decrease in the AAT-120 group (−0.29 pmol/mL, p = 0.047). The mean HbA1c level was significantly lower in the AAT-120 group compared to the placebo (6.7% ± 0.9% vs. 8.2 ± 1.4%, p = 0.05), and a higher percentage of patients attained HbA1c ≤ 7% (75% vs. 25%, p = 0.05). AAT was tolerated well, with a similar safety profile between groups. The AAT intervention showed promise in the subgroup of adolescents with recent-onset type 1 diabetes. Further studies are warranted to determine the impact and proposed mechanism of action of AAT in β-cell preservation. Full article
(This article belongs to the Special Issue Advances in Immunotherapeutic Approaches to Type 1 Diabetes)
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13 pages, 2987 KiB  
Communication
BET Proteins Are Required for Transcriptional Activation of the Senescent Islet Cell Secretome in Type 1 Diabetes
by Peter J. Thompson, Ajit Shah, Hara Apostolopolou and Anil Bhushan
Int. J. Mol. Sci. 2019, 20(19), 4776; https://doi.org/10.3390/ijms20194776 - 26 Sep 2019
Cited by 32 | Viewed by 3781
Abstract
Type 1 diabetes (T1D) results from the progressive loss of pancreatic beta cells as a result of autoimmune destruction. We recently reported that during the natural history of T1D in humans and the female nonobese diabetic (NOD) mouse model, beta cells acquire a [...] Read more.
Type 1 diabetes (T1D) results from the progressive loss of pancreatic beta cells as a result of autoimmune destruction. We recently reported that during the natural history of T1D in humans and the female nonobese diabetic (NOD) mouse model, beta cells acquire a senescence-associated secretory phenotype (SASP) that is a major driver of disease onset and progression, but the mechanisms that activate SASP in beta cells were not explored. Here, we show that the SASP in islet cells is transcriptionally controlled by Bromodomain ExtraTerminal (BET) proteins, including Bromodomain containing protein 4 (BRD4). A chromatin analysis of key beta cell SASP genes in NOD islets revealed binding of BRD4 at active regulatory regions. BET protein inhibition in NOD islets diminished not only the transcriptional activation and secretion of SASP factors, but also the non-cell autonomous activity. BET protein inhibition also decreased the extent of SASP induction in human islets exposed to DNA damage. The BET protein inhibitor iBET-762 prevented diabetes in NOD mice and also attenuated SASP in islet cells in vivo. Taken together, our findings support a crucial role for BET proteins in the activation of the SASP transcriptional program in islet cells. These studies suggest avenues for preventing T1D by transcriptional inhibition of SASP. Full article
(This article belongs to the Special Issue Advances in Immunotherapeutic Approaches to Type 1 Diabetes)
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Review

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11 pages, 232 KiB  
Review
Immunotherapy Strategies for the Prevention and Treatment of Distinct Stages of Type 1 Diabetes: An Overview
by Novella Rapini, Riccardo Schiaffini and Alessandra Fierabracci
Int. J. Mol. Sci. 2020, 21(6), 2103; https://doi.org/10.3390/ijms21062103 - 19 Mar 2020
Cited by 21 | Viewed by 4345
Abstract
Type 1 diabetes mellitus is a heterogeneous disorder characterized by destruction of pancreatic β cells, culminating in absolute insulin deficiency. The goals of Type 1 diabetes care, established by the Diabetes Control and Complications Trial (DCCT), are to achieve good glycemic control, to [...] Read more.
Type 1 diabetes mellitus is a heterogeneous disorder characterized by destruction of pancreatic β cells, culminating in absolute insulin deficiency. The goals of Type 1 diabetes care, established by the Diabetes Control and Complications Trial (DCCT), are to achieve good glycemic control, to prevent hyperglycaemia (which is associated with long-term microvascular and macrovascular complications) and to avoid recurrent episodes of hypoglycaemia (which may have adverse effects on cognitive function). However, despite continuing optimization of insulin therapy regimes, the actual hormonal substitutive administration acts only to treat the symptoms without an effect on disease pathology and etiopathogenesis. In recent decades, a great deal of interest has been focused on prevention approaches in high-risk individuals, based on the hypothesis that a therapeutic intervention, if applied at the early stage of disease, might contribute to maintaining endogenous β cell function by preserving the residual β cell reservoir from autoimmune attack. This manuscript provides an overview of the most important immunotherapeutic interventions established so far for Type 1 diabetes treatment at different stages of disease that have reached an advanced stage of assessment. Full article
(This article belongs to the Special Issue Advances in Immunotherapeutic Approaches to Type 1 Diabetes)
20 pages, 679 KiB  
Review
Autoantigen Treatment in Type 1 Diabetes: Unsolved Questions on How to Select Autoantigen and Administration Route
by Johnny Ludvigsson
Int. J. Mol. Sci. 2020, 21(5), 1598; https://doi.org/10.3390/ijms21051598 - 26 Feb 2020
Cited by 29 | Viewed by 5588
Abstract
Autoantigen treatment has been tried for the prevention of type 1 diabetes (T1D) and to preserve residual beta-cell function in patients with a recent onset of the disease. In experimental animal models, efficacy was good, but was insufficient in human subjects. Besides the [...] Read more.
Autoantigen treatment has been tried for the prevention of type 1 diabetes (T1D) and to preserve residual beta-cell function in patients with a recent onset of the disease. In experimental animal models, efficacy was good, but was insufficient in human subjects. Besides the possible minor efficacy of peroral insulin in high-risk individuals to prevent T1D, autoantigen prevention trials have failed. Other studies on autoantigen prevention and intervention at diagnosis are ongoing. One problem is to select autoantigen/s; others are dose and route. Oral administration may be improved by using different vehicles. Proinsulin peptide therapy in patients with T1D has shown possible minor efficacy. In patients with newly diagnosed T1D, subcutaneous injection of glutamic acid decarboxylase (GAD) bound to alum hydroxide (GAD-alum) can likely preserve beta-cell function, but the therapeutic effect needs to be improved. Intra-lymphatic administration may be a better alternative than subcutaneous administration, and combination therapy might improve efficacy. This review elucidates some actual problems of autoantigen therapy in the prevention and/or early intervention of type 1 diabetes. Full article
(This article belongs to the Special Issue Advances in Immunotherapeutic Approaches to Type 1 Diabetes)
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15 pages, 2937 KiB  
Review
Pharmacological Targeting of GLUT1 to Control Autoreactive T Cell Responses
by Carla Di Dedda, Debora Vignali, Lorenzo Piemonti and Paolo Monti
Int. J. Mol. Sci. 2019, 20(19), 4962; https://doi.org/10.3390/ijms20194962 - 8 Oct 2019
Cited by 31 | Viewed by 10321
Abstract
An increasing body of evidence indicates that bio-energetic metabolism of T cells can be manipulated to control T cell responses. This potentially finds a field of application in the control of the T cell responses in autoimmune diseases, including in type 1 diabetes [...] Read more.
An increasing body of evidence indicates that bio-energetic metabolism of T cells can be manipulated to control T cell responses. This potentially finds a field of application in the control of the T cell responses in autoimmune diseases, including in type 1 diabetes (T1D). Of the possible metabolic targets, Glut1 gained considerable interest because of its pivotal role in glucose uptake to fuel glycolysis in activated T cells, and the recent development of a novel class of small molecules that act as selective inhibitor of Glut1. We believe we can foresee a possible application of pharmacological Glut1 blockade approach to control autoreactive T cells that destroy insulin producing beta cells. However, Glut1 is expressed in a broad range of cells in the body and off-target and side effect are possible complications. Moreover, the duration of the treatment and the age of patients are critical aspects that need to be addressed to reduce toxicity. In this paper, we will review recent literature to determine whether it is possible to design a pharmacological Glut1 blocking strategy and how to apply this to autoimmunity in T1D. Full article
(This article belongs to the Special Issue Advances in Immunotherapeutic Approaches to Type 1 Diabetes)
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26 pages, 950 KiB  
Review
New Insights into Immunotherapy Strategies for Treating Autoimmune Diabetes
by Miriam Cabello-Olmo, Miriam Araña, Ilian Radichev, Paul Smith, Eduardo Huarte and Miguel Barajas
Int. J. Mol. Sci. 2019, 20(19), 4789; https://doi.org/10.3390/ijms20194789 - 26 Sep 2019
Cited by 25 | Viewed by 8183
Abstract
Type 1 diabetes mellitus (T1D) is an autoimmune illness that affects millions of patients worldwide. The main characteristic of this disease is the destruction of pancreatic insulin-producing beta cells that occurs due to the aberrant activation of different immune effector cells. Currently, T1D [...] Read more.
Type 1 diabetes mellitus (T1D) is an autoimmune illness that affects millions of patients worldwide. The main characteristic of this disease is the destruction of pancreatic insulin-producing beta cells that occurs due to the aberrant activation of different immune effector cells. Currently, T1D is treated by lifelong administration of novel versions of insulin that have been developed recently; however, new approaches that could address the underlying mechanisms responsible for beta cell destruction have been extensively investigated. The strategies based on immunotherapies have recently been incorporated into a panel of existing treatments for T1D, in order to block T-cell responses against beta cell antigens that are very common during the onset and development of T1D. However, a complete preservation of beta cell mass as well as insulin independency is still elusive. As a result, there is no existing T1D targeted immunotherapy able to replace standard insulin administration. Presently, a number of novel therapy strategies are pursuing the goals of beta cell protection and normoglycemia. In the present review we explore the current state of immunotherapy in T1D by highlighting the most important studies in this field, and envision novel strategies that could be used to treat T1D in the future. Full article
(This article belongs to the Special Issue Advances in Immunotherapeutic Approaches to Type 1 Diabetes)
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