Progress in Translational Regulatory T Cell Therapies for Type 1 Diabetes and Islet Transplantation

2020 ◽  
Author(s):  
Braulio A Marfil-Garza ◽  
Joshua Hefler ◽  
Mario Bermudez De Leon ◽  
Rena Pawlick ◽  
Nidheesh Dadheech ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Islet Transplantation ◽  
Ex Vivo ◽  
Severe Hypoglycemia ◽  
Cell Therapies ◽  
Current State ◽  
Cellular Transplantation ◽  
And Function

Abstract Regulatory T cells (Tregs) have become highly relevant in the pathophysiology and treatment of autoimmune diseases, such as type 1 diabetes (T1D). As these cells are known to be defective in T1D, recent efforts have explored ex vivo and in vivo Treg expansion and enhancement as a means for restoring self-tolerance in this disease. Given their capacity to also modulate alloimmune responses, studies using Treg-based therapies have recently been undertaken in transplantation. Islet transplantation provides a unique opportunity to study the critical immunological crossroads between auto- and alloimmunity. This procedure has advanced greatly in recent years, and reports of complete abrogation of severe hypoglycemia and long-term insulin independence have become increasingly reported. It is clear that cellular transplantation has the potential to be a true cure in T1D, provided the remaining barriers of cell supply and abrogated need for immune suppression can be overcome. However, the role that Tregs play in islet transplantation remains to be defined. Herein, we synthesize the progress and current state of Treg-based therapies in T1D and islet transplantation. We provide an extensive, but concise, background to understand the physiology and function of these cells and discuss the clinical evidence supporting potency and potential Treg-based therapies in the context of T1D and islet transplantation. Finally, we discuss some areas of opportunity and potential research avenues to guide effective future clinical application. This review provides a basic framework of knowledge for clinicians and researchers involved in the care of patients with T1D and islet transplantation.

scholarly journals Overview of Cellular Transplantation in Diabetes Mellitus: Focus on the Metabolic Outcome

2015 ◽  
Vol 2015 ◽  
pp. 1-8
Author(s):  
Livio Luzi ◽  
Stefano Benedini ◽  
Andrea Caumo ◽  
Ileana Terruzzi
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Type 1 Diabetes Mellitus ◽  
Islet Transplantation ◽  
Immunosuppressive Drugs ◽  
Cell Therapies ◽  
Cellular Transplantation ◽  
Major Disadvantage ◽  
Pancreas Islet

Diabetes mellitus is a metabolic disease possible to treat via several different therapeutic approaches. Since the advent of insulin in 1922, type 1 diabetes mellitus has become a chronic treatable disease. Nonetheless, type 1 diabetes mellitus can be a devastating disease when the macro- and microangiopathic complications take place after several years of illness. Starting from the eighties, pancreas/islet transplantation has become a potential innovative treatment of diabetes mellitus. The major advantage of pancreas/islet transplantation is the restoration of c-peptide cosecretion along with insulin; the major disadvantage is the need to administer immunosuppressive drugs which are diabetogenic themselves. Islet transplantation is the progenitor of more recent forms of cellular and stem cell therapies which will be reviewed herein. Cellular therapies for diabetes mellitus are still an experimental procedure. Herein we present the actual current achievements and an outlook of close future possible advancements in the area of cellular transplantation for the cure of diabetes mellitus.

scholarly journals Mortality in People With Type 1 Diabetes, Severe Hypoglycemia, and Impaired Awareness of Hypoglycemia Referred for Islet Transplantation

2018 ◽  
Vol 4 (11) ◽  
pp. e401 ◽  
Author(s):  
Melissa H. Lee ◽  
Glenn M. Ward ◽  
Richard J. MacIsaac ◽  
Kathy Howe ◽  
D. Jane Holmes-Walker ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Islet Transplantation ◽  
Severe Hypoglycemia ◽  
Impaired Awareness

scholarly journals Exocytosis Protein DOC2B as a Biomarker of Type 1 Diabetes

2018 ◽  
Vol 103 (5) ◽  
pp. 1966-1976 ◽  
Author(s):  
Arianne Aslamy ◽  
Eunjin Oh ◽  
Miwon Ahn ◽  
Abu Saleh Md Moin ◽  
Mariann Chang ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Islet Transplantation ◽  
Ex Vivo ◽  
Human Subjects ◽  
Cell Mass ◽  
Nod Mice ◽  
Human Islets ◽  
Β Cell ◽  
New Onset

Abstract Context Efforts to preserve β-cell mass in the preclinical stages of type 1 diabetes (T1D) are limited by few blood-derived biomarkers of β-cell destruction. Objective Platelets are proposed sources of blood-derived biomarkers for a variety of diseases, and they show distinct proteomic changes in T1D. Thus, we investigated changes in the exocytosis protein, double C2 domain protein-β (DOC2B) in platelets and islets from T1D humans, and prediabetic nonobese diabetic (NOD) mice. Design, Patients, and Main Outcome Measure Protein levels of DOC2B were assessed in platelets and islets from prediabetic NOD mice and humans, with and without T1D. Seventeen new-onset T1D human subjects (10.3 ± 3.8 years) were recruited immediately following diagnosis, and platelet DOC2B levels were compared with 14 matched nondiabetic subjects (11.4 ± 2.9 years). Furthermore, DOC2B levels were assessed in T1D human pancreatic tissue samples, cytokine-stimulated human islets ex vivo, and platelets from T1D subjects before and after islet transplantation. Results DOC2B protein abundance was substantially reduced in prediabetic NOD mouse platelets, and these changes were mirrored in the pancreatic islets from the same mice. Likewise, human DOC2B levels were reduced over twofold in platelets from new-onset T1D human subjects, and this reduction was mirrored in T1D human islets. Cytokine stimulation of normal islets reduced DOC2B expression ex vivo. Remarkably, platelet DOC2B levels increased after islet transplantation in patients with T1D. Conclusions Reduction of DOC2B is an early feature of T1D, and DOC2B abundance may serve as a valuable in vivo indicator of β-cell mass and an early biomarker of T1D.

scholarly journals Improved Health-Related Quality of Life in a Phase 3 Islet Transplantation Trial in Type 1 Diabetes Complicated by Severe Hypoglycemia

Diabetes Care ◽  
2018 ◽  
Vol 41 (5) ◽  
pp. 1001-1008 ◽  
Author(s):  
Eric D. Foster ◽  
Nancy D. Bridges ◽  
Irene D. Feurer ◽  
Thomas L. Eggerman ◽  
Lawrence G. Hunsicker ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Type 1 Diabetes ◽  
Islet Transplantation ◽  
Severe Hypoglycemia ◽  
Health Related Quality ◽  
Phase 3 ◽  
Related Quality ◽  
Health Related

scholarly journals A high glycemic burden relates to functional and metabolic alterations of human monocytes in patients with type 1 diabetes

2020 ◽  
Author(s):  
Ada Admin ◽  
Kathrin Thiem ◽  
Xanthe A.M.H. van Dierendonck ◽  
Anna W.M. Janssen ◽  
Joline P. Boogaard ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Innate Immune System ◽  
Ex Vivo ◽  
Innate Immune ◽  
Transcriptome Profile ◽  
Inflammatory Gene Expression ◽  
Patients With Diabetes ◽  
And Function ◽  
Glycolytic Rate

Diabetes mellitus is associated with increased cardiovascular risk and higher occurrence of infections. These complications suggest altered responses of the innate immune system. Recent studies have shown that energy metabolism of monocytes is crucial in determining their functionality. Here we investigate whether monocyte metabolism and function are changed in patients with diabetes and aim to identify diabetes-associated factors driving these alterations. Patients with type 1 diabetes (T1D) (n=41) and healthy age-, sex- and BMI-matched controls (n=20) were recruited. Monocytes were isolated from peripheral blood to determine immune functionality, metabolic responses and transcriptome profile. Upon <i>ex vivo</i> stimulation with TLR-4 or TLR-2 agonists, monocytes of patients with T1D secreted lower levels of various cytokines and showed lower glycolytic rates in comparison to monocytes isolated from matched controls. Stratification based on HbA<sub>1c</sub> levels revealed that lower cytokine secretion was coupled to higher glycolytic rate of monocytes in patients with higher glycemic burden. Circulating monocytes displayed an enhanced inflammatory gene expression profile associated with high glycemic burden. These results suggest that a high glycemic burden in patients with T1D is related to expression of inflammatory genes of monocytes and is associated with an impaired relationship between metabolism and inflammatory function upon activation.

217-OR: Islet Transplantation vs. Standard of Care for Type 1 Diabetes Complicated by Severe Hypoglycemia from the Collaborative Islet Transplant Registry (CITR) and T1D Exchange (T1DX) Registry

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 217-OR
Author(s):  
MICHAEL R. RICKELS ◽  
NICOLE C. FOSTER ◽  
CASSANDRA M. BALLOU ◽  
BERNHARD J. HERING ◽  
RODOLFO ALEJANDRO ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Islet Transplantation ◽  
Severe Hypoglycemia ◽  
Standard Of Care ◽  
Islet Transplant ◽  
Transplant Registry ◽  
Islet Transplant Registry

scholarly journals Subcutaneous transplantation of embryonic pancreas for correction of type 1 diabetes

2009 ◽  
Vol 296 (2) ◽  
pp. E323-E332 ◽  
Author(s):  
Subhadra C. Gunawardana ◽  
Richard K. P. Benninger ◽  
David W. Piston
Keyword(s):  
Type 1 Diabetes ◽  
Islet Transplantation ◽  
Invasive Surgery ◽  
Imaging Techniques ◽  
Pancreatic Tissue ◽  
Endocrine Differentiation ◽  
Promising Therapeutic Approach ◽  
Subcutaneous Space

Islet transplantation is a promising therapeutic approach for type 1 diabetes. However, current success rates are low due to progressive graft failure in the long term and inability to monitor graft development in vivo. Other limitations include the necessity of initial invasive surgery and continued immunosuppressive therapy. We report an alternative transplantation strategy with the potential to overcome these problems. This technique involves transplantation of embryonic pancreatic tissue into recipients’ subcutaneous space, eliminating the need for invasive surgery and associated risks. Current results in mouse models of type 1 diabetes show that embryonic pancreatic transplants in the subcutaneous space can normalize blood glucose homeostasis and achieve extensive endocrine differentiation and vascularization. Furthermore, modern imaging techniques such as two-photon excitation microscopy (TPEM) can be employed to monitor transplants through the intact skin in a completely noninvasive manner. Thus, this strategy is a convenient alternative to islet transplantation in diabetic mice and has the potential to be translated to human clinical applications with appropriate modifications.

scholarly journals A high glycemic burden relates to functional and metabolic alterations of human monocytes in patients with type 1 diabetes

2020 ◽  
Author(s):  
Ada Admin ◽  
Kathrin Thiem ◽  
Xanthe A.M.H. van Dierendonck ◽  
Anna W.M. Janssen ◽  
Joline P. Boogaard ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Innate Immune System ◽  
Ex Vivo ◽  
Innate Immune ◽  
Transcriptome Profile ◽  
Inflammatory Gene Expression ◽  
Patients With Diabetes ◽  
And Function ◽  
Glycolytic Rate

Diabetes mellitus is associated with increased cardiovascular risk and higher occurrence of infections. These complications suggest altered responses of the innate immune system. Recent studies have shown that energy metabolism of monocytes is crucial in determining their functionality. Here we investigate whether monocyte metabolism and function are changed in patients with diabetes and aim to identify diabetes-associated factors driving these alterations. Patients with type 1 diabetes (T1D) (n=41) and healthy age-, sex- and BMI-matched controls (n=20) were recruited. Monocytes were isolated from peripheral blood to determine immune functionality, metabolic responses and transcriptome profile. Upon <i>ex vivo</i> stimulation with TLR-4 or TLR-2 agonists, monocytes of patients with T1D secreted lower levels of various cytokines and showed lower glycolytic rates in comparison to monocytes isolated from matched controls. Stratification based on HbA<sub>1c</sub> levels revealed that lower cytokine secretion was coupled to higher glycolytic rate of monocytes in patients with higher glycemic burden. Circulating monocytes displayed an enhanced inflammatory gene expression profile associated with high glycemic burden. These results suggest that a high glycemic burden in patients with T1D is related to expression of inflammatory genes of monocytes and is associated with an impaired relationship between metabolism and inflammatory function upon activation.

scholarly journals Considerations and Challenges of Islet Transplantation and Future Therapies on the Horizon

2021 ◽  
Author(s):  
Sophie Walker ◽  
Mahesh Appari ◽  
Shareen Forbes
Keyword(s):  
Type 1 Diabetes ◽  
Islet Transplantation ◽  
Clinical Stage ◽  
Embryonic Stem ◽  
Outcome Data ◽  
Cell Therapies ◽  
Islet Transplant ◽  
Systemic Immunosuppression ◽  
Stage Of Development

Islet transplantation is a treatment for selected adults with Type 1 diabetes and severe hypoglycemia. Islets from two or more donor pancreases, a scarce resource, are usually required to impact on glycemic control but the treatment falls short of a cure. Islets are avascular when transplanted into the hypoxic liver environment and subjected to inflammatory insults, immune attack and toxicity from systemic immunosuppression. The Collaborative Islet Transplant Registry with outcome data on over 1000 islet transplant recipients has demonstrated that larger islet numbers transplanted and older age of recipient are associated with better outcomes. Induction with T cell depleting agents and the TNF-α inhibitor Etanercept and maintenance systemic immunosuppression with mTOR inhibitors in combination with calcineurin inhibitors also appear advantageous, but concerns remain over immunosuppressive toxicity. We discuss strategies and therapeutics which address specific challenges of islet transplantation, many of which are at the pre-clinical stage of development. On the horizon are adjuvant cell therapies with mesenchymal stromal cells and regulatory T cells that have been used in preclinical models and in humans in other contexts; such a strategy may enable reductions in immunosuppression in the early peri-transplant period when the islets are vulnerable to apoptosis. Human embryonic stem-cell derived islets are in early phase clinical trials and hold the promise of an inexhaustible supply of insulin producing cells; effective encapsulation of such cells or, silencing of the HLA complex would eliminate the need for immunosuppression, enabling this therapy to be used in all those with Type 1 diabetes.

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