|
1
|
Foster TP, Bruggeman BS, Haller MJ. Emerging Immunotherapies for Disease Modification of Type 1 Diabetes. Drugs 2025; 85:457-473. [PMID: 39873914 PMCID: PMC11949705 DOI: 10.1007/s40265-025-02150-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/13/2025] [Indexed: 01/30/2025]
Abstract
Type 1 diabetes mellitus (T1DM) is characterized by the progressive, autoimmune-mediated destruction of β cells. As such, restoring immunoregulation early in the disease course is sought to retain endogenous insulin production. Nevertheless, in the more than 100 years since the discovery of insulin, treatment of T1DM has focused primarily on hormone replacement and glucose monitoring. That said, immunotherapies are widely used to interdict autoimmune and autoinflammatory diseases and are emerging as potential therapeutics seeking the preservation of β-cell function among those with T1DM. In the past 4 decades of diabetes research, several immunomodulatory therapies have been explored, culminating with the US Food and Drug Administration approval of teplizumab to delay stage 3 (clinical) onset of T1DM. Clinical trials seeking to prevent or reverse T1DM by repurposing immunotherapies approved for other autoimmune conditions and by exploring new therapeutics are ongoing. Collectively, these efforts have the potential to transform the future of diabetes care. We encapsulate the past 40 years of immunotherapy trials, take stock of our successes and failures, and chart paths forward in this new age of clinically available immune therapies for T1DM.
Collapse
Affiliation(s)
- Timothy P Foster
- Division of Endocrinology, Department of Pediatrics, College of Medicine, University of Florida, 1699 SW 16th Ave, Building A, Gainesville, FL, 32608, USA.
| | - Brittany S Bruggeman
- Division of Endocrinology, Department of Pediatrics, College of Medicine, University of Florida, 1699 SW 16th Ave, Building A, Gainesville, FL, 32608, USA
| | - Michael J Haller
- Division of Endocrinology, Department of Pediatrics, College of Medicine, University of Florida, 1699 SW 16th Ave, Building A, Gainesville, FL, 32608, USA
- Department of Pathology, Immunology, and Laboratory Medicine, Diabetes Institute, University of Florida, Gainesville, FL, USA
| |
Collapse
|
|
2
|
Jeun R. Immunotherapies for prevention and treatment of type 1 diabetes. Immunotherapy 2025; 17:201-210. [PMID: 40033931 PMCID: PMC11951698 DOI: 10.1080/1750743x.2025.2473311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 02/25/2025] [Indexed: 03/05/2025] Open
Abstract
Type 1 diabetes (T1D) is characterized by the autoimmune destruction of insulin-producing β-cells of the pancreatic islets necessitating lifelong insulin therapy. Despite significant advancements in diabetes technology with increasingly sophisticated methods of insulin delivery and glucose monitoring, people with T1D remain at risk of severe complications like hypoglycemia and diabetic ketoacidosis. There has long been an interest in altering the immune response in T1D to prevent or cure T1D across its various stages with limited efficacy. This review highlights immunomodulatory approaches over the years including the anti-CD3 monoclonal antibody teplizumab which is now approved to delay onset of T1DM and other interventions under current investigation.
Collapse
Affiliation(s)
- Rebecca Jeun
- Division of Endocrinology, Diabetes & Metabolism, University of Louisville, Louisville, KY, USA
| |
Collapse
|
|
3
|
Salah AN, Hashem AH, Zaki MB, Abulsoud AI, Atta AM, Elkalla WS, Moustafa HAM, El-Dakroury WA, El-Tokhy FS, ElBoghdady JA, Rizk NI, Abdel Mageed SS, Mohammed OA, Abdel-Reheim MA, Alghamdi HO, Doghish AS. Targeted Therapies: The Role of Monoclonal Antibodies in Disease Management. J Biochem Mol Toxicol 2025; 39:e70163. [PMID: 39887821 DOI: 10.1002/jbt.70163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 12/28/2024] [Accepted: 01/20/2025] [Indexed: 02/01/2025]
Abstract
Monoclonal antibodies (mAbs) are a key class of biotherapeutic medicines used to treat a wide range of diseases, such as cancer, infectious diseases, autoimmune disorders, cardiovascular diseases, and hemophilia. They can be engineered for greater effectiveness and specific applications while maintaining their structural elements for immune targeting. Traditional immunoglobulin treatments have limited therapeutic uses and various adverse effects. That makes mAbs show rapid growth in the pharmaceutical market, with over 250 mAbs in clinical studies. Although mAbs offer higher specificity, they are less effective against complex antigens. They have become essential in treating diseases with limited medical options, providing innovative solutions that improve patients' quality of life through increasing survival rates, shortening the length of stay in hospitals with an improved treatment outcome, and reducing side effects. This review outlines the mechanisms, applications, and advancements of mAbs, highlighting their transformative role in modern medicine and their potential to shape future therapeutic interventions.
Collapse
Affiliation(s)
- Akram N Salah
- Microbiology and Immunology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Amr H Hashem
- Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Nasr City, 11884, Egypt
| | - Mohamed Bakr Zaki
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Menofia, 32897, Egypt
- Department of Biochemistry, Faculty of Pharmacy, Menoufia National University, km Cairo-Alexandria Agricultural Road, Menofia, Egypt
| | - Ahmed I Abulsoud
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo, 11785, Egypt
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt
| | - Asmaa M Atta
- Pharmaceutical Chemistry Department, School of Pharmacy, Badr University in Cairo (BUC), Badr City, Egypt
| | - Wagiha S Elkalla
- Microbiology and Immunology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Hebatallah Ahmed Mohamed Moustafa
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Walaa A El-Dakroury
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Fatma Sa'eed El-Tokhy
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Jasmine A ElBoghdady
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Nehal I Rizk
- Department of Biochemistry, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, Cairo, 11786, Egypt
| | - Sherif S Abdel Mageed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Osama A Mohammed
- Department of Pharmacology, College of Medicine, University of Bisha, Bisha, 61922, Saudi Arabia
| | | | - Huda O Alghamdi
- College of Medicine, University of Bisha, Bisha, 61922, Saudi Arabia
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Egypt
- Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt
| |
Collapse
|
|
4
|
Ma H, Xu J, Fang H, Su Y, Lu Y, Shu Y, Liu W, Li B, Cheng YY, Nie Y, Zhong Y, Song K. A capsule-based scaffold incorporating decellularized extracellular matrix and curcumin for islet beta cell therapy in type 1 diabetes mellitus. Biofabrication 2024; 16:045038. [PMID: 39255833 DOI: 10.1088/1758-5090/ad7907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 09/10/2024] [Indexed: 09/12/2024]
Abstract
The transplantation of islet beta cells offers an alternative to heterotopic islet transplantation for treating type 1 diabetes mellitus (T1DM). However, the use of systemic immunosuppressive drugs in islet transplantation poses significant risks to the body. To address this issue, we constructed an encapsulated hybrid scaffold loaded with islet beta cells. This article focuses on the preparation of the encapsulated structure using 3D printing, which incorporates porcine pancreas decellularized extracellular matrix (dECM) to the core scaffold. The improved decellularization method successfully preserved a substantial proportion of protein (such as Collagen I and Laminins) architecture and glycosaminoglycans in the dECM hydrogel, while effectively removing most of the DNA. The inclusion of dECM enhanced the physical and chemical properties of the scaffold, resulting in a porosity of 83.62% ± 1.09% and a tensile stress of 1.85 ± 0.16 MPa. In teams of biological activity, dECM demonstrated enhanced proliferation, differentiation, and expression of transcription factors such as Ki67, PDX1, and NKX6.1, leading to improved insulin secretion function in MIN-6 pancreatic beta cells. In the glucose-stimulated insulin secretion experiment on day 21, the maximum insulin secretion from the encapsulated structure reached 1.96 ± 0.08 mIU ml-1, representing a 44% increase compared to the control group. Furthermore, conventional capsule scaffolds leaverage the compatibility of natural biomaterials with macrophages to mitigate immune rejection. Here, incorporating curcumin into the capsule scaffold significantly reduced the secretion of pro-inflammatory cytokine (IL-1β, IL-6, TNF-α, IFN-γ) secretion by RAW264.7 macrophages and T cells in T1DM mice. This approach protected pancreatic islet cells against immune cell infiltration mediated by inflammatory factors and prevented insulitis. Overall, the encapsulated scaffold developed in this study shows promise as a natural platform for clinical treatment of T1DM.
Collapse
Affiliation(s)
- Hailin Ma
- State Key Laboratory of Fine Chemicals, Dalian R&D Center for Stem Cell and Tissue Engineering, Dalian University of Technology, Dalian 116024, People's Republic of China
- Zhengzhou Institute of Emerging Industrial Technology, Zhengzhou 450000, People's Republic of China
| | - Jie Xu
- State Key Laboratory of Fine Chemicals, Dalian R&D Center for Stem Cell and Tissue Engineering, Dalian University of Technology, Dalian 116024, People's Republic of China
- Zhengzhou Institute of Emerging Industrial Technology, Zhengzhou 450000, People's Republic of China
| | - Huan Fang
- State Key Laboratory of Fine Chemicals, Dalian R&D Center for Stem Cell and Tissue Engineering, Dalian University of Technology, Dalian 116024, People's Republic of China
- Zhengzhou Institute of Emerging Industrial Technology, Zhengzhou 450000, People's Republic of China
| | - Ya Su
- State Key Laboratory of Fine Chemicals, Dalian R&D Center for Stem Cell and Tissue Engineering, Dalian University of Technology, Dalian 116024, People's Republic of China
| | - Yueqi Lu
- State Key Laboratory of Fine Chemicals, Dalian R&D Center for Stem Cell and Tissue Engineering, Dalian University of Technology, Dalian 116024, People's Republic of China
- Zhengzhou Institute of Emerging Industrial Technology, Zhengzhou 450000, People's Republic of China
| | - Yan Shu
- State Key Laboratory of Fine Chemicals, Dalian R&D Center for Stem Cell and Tissue Engineering, Dalian University of Technology, Dalian 116024, People's Republic of China
| | - Wang Liu
- State Key Laboratory of Fine Chemicals, Dalian R&D Center for Stem Cell and Tissue Engineering, Dalian University of Technology, Dalian 116024, People's Republic of China
| | - Bing Li
- State Key Laboratory of Fine Chemicals, Dalian R&D Center for Stem Cell and Tissue Engineering, Dalian University of Technology, Dalian 116024, People's Republic of China
| | - Yuen Yee Cheng
- Institute for Biomedical Materials and Devices, Faculty of Science, University of Technology, Sydney, NSW 2007, Australia
| | - Yi Nie
- Zhengzhou Institute of Emerging Industrial Technology, Zhengzhou 450000, People's Republic of China
| | - Yiming Zhong
- Department of Hand and Foot Microsurgery, Dalian Municipal Central Hospital Affiliated of Dalian University of Technology, Dalian 116033, People's Republic of China
| | - Kedong Song
- State Key Laboratory of Fine Chemicals, Dalian R&D Center for Stem Cell and Tissue Engineering, Dalian University of Technology, Dalian 116024, People's Republic of China
- Zhengzhou Institute of Emerging Industrial Technology, Zhengzhou 450000, People's Republic of China
| |
Collapse
|
|
5
|
Zhao L, Hu H, Zhang L, Liu Z, Huang Y, Liu Q, Jin L, Zhu M, Zhang L. Inflammation in diabetes complications: molecular mechanisms and therapeutic interventions. MedComm (Beijing) 2024; 5:e516. [PMID: 38617433 PMCID: PMC11014467 DOI: 10.1002/mco2.516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Revised: 02/16/2024] [Accepted: 02/21/2024] [Indexed: 04/16/2024] Open
Abstract
At present, diabetes mellitus (DM) has been one of the most endangering healthy diseases. Current therapies contain controlling high blood sugar, reducing risk factors like obesity, hypertension, and so on; however, DM patients inevitably and eventually progress into different types of diabetes complications, resulting in poor quality of life. Unfortunately, the clear etiology and pathogenesis of diabetes complications have not been elucidated owing to intricate whole-body systems. The immune system was responsible to regulate homeostasis by triggering or resolving inflammatory response, indicating it may be necessary to diabetes complications. In fact, previous studies have been shown inflammation plays multifunctional roles in the pathogenesis of diabetes complications and is attracting attention to be the meaningful therapeutic strategy. To this end, this review systematically concluded the current studies over the relationships of susceptible diabetes complications (e.g., diabetic cardiomyopathy, diabetic retinopathy, diabetic peripheral neuropathy, and diabetic nephropathy) and inflammation, ranging from immune cell response, cytokines interaction to pathomechanism of organ injury. Besides, we also summarized various therapeutic strategies to improve diabetes complications by target inflammation from special remedies to conventional lifestyle changes. This review will offer a panoramic insight into the mechanisms of diabetes complications from an inflammatory perspective and also discuss contemporary clinical interventions.
Collapse
Affiliation(s)
- Lu Zhao
- Department of Biology and MedicineCollege of Life Science, Zhejiang Chinese Medical UniversityHangzhouChina
| | - Haoran Hu
- Department of Biology and MedicineCollege of Life Science, Zhejiang Chinese Medical UniversityHangzhouChina
| | - Lin Zhang
- Department of Biology and MedicineCollege of Life Science, Zhejiang Chinese Medical UniversityHangzhouChina
| | - Zheting Liu
- Department of Biology and MedicineCollege of Life Science, Zhejiang Chinese Medical UniversityHangzhouChina
| | - Yunchao Huang
- Department of Biology and MedicineCollege of Life Science, Zhejiang Chinese Medical UniversityHangzhouChina
| | - Qian Liu
- National Demonstration Center for Experimental Traditional Chinese Medicines Education (Zhejiang Chinese Medical University)College of Pharmaceutical Science, Zhejiang Chinese Medical UniversityHangzhouChina
| | - Liang Jin
- Department of Biology and MedicineCollege of Life Science, Zhejiang Chinese Medical UniversityHangzhouChina
- Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia MedicaShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Meifei Zhu
- Department of Critical Care MedicineThe First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)HangzhouChina
| | - Ling Zhang
- Department of Biology and MedicineCollege of Life Science, Zhejiang Chinese Medical UniversityHangzhouChina
| |
Collapse
|
|
6
|
Ashraf MT, Ahmed Rizvi SH, Kashif MAB, Shakeel Khan MK, Ahmed SH, Asghar MS. Efficacy of anti-CD3 monoclonal antibodies in delaying the progression of recent-onset type 1 diabetes mellitus: A systematic review, meta-analyses and meta-regression. Diabetes Obes Metab 2023; 25:3377-3389. [PMID: 37580969 DOI: 10.1111/dom.15237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 07/11/2023] [Accepted: 07/22/2023] [Indexed: 08/16/2023]
Abstract
AIM Type 1 diabetes mellitus is widely recognized as a chronic autoimmune disease characterized by the pathogenic destruction of beta cells, resulting in the loss of endogenous insulin production. Insulin administration remains the primary therapy for symptomatic treatment. Recent studies showed that disease-modifying agents, such as anti-CD3 monoclonal antibodies, have shown promising outcomes in improving the management of the disease. In late 2022, teplizumab received approval from the US Food and Drug Administration (FDA) as the first disease-modifying agent for the treatment of type 1 diabetes. This review aims to evaluate the clinical evidence regarding the efficacy of anti-CD3 monoclonal antibodies in the prevention and treatment of type 1 diabetes. METHODS A comprehensive search of PubMed, Google Scholar, Scopus and Cochrane Central Register of Controlled Trials (CENTRAL) was conducted up to December 2022 to identify relevant randomized controlled trials. Meta-analysis was performed using a random-effects model, and odds ratios with 95% confidence intervals (CIs) were calculated to quantify the effects. The Cochrane risk of bias tool was employed for quality assessment. RESULTS In total, 11 randomized controlled trials involving 1397 participants (908 participants in the intervention arm, 489 participants in the control arm) were included in this review. The mean age of participants was 15 years, and the mean follow-up time was 2.04 years. Teplizumab was the most commonly studied intervention. Compared with placebo, anti-CD3 monoclonal antibody treatment significantly increased the C-peptide concentration in the area under the curve at shorter timeframes (mean difference = 0.114, 95% CI: 0.069 to 0.159, p = .000). Furthermore, anti-CD3 monoclonal antibodies significantly reduced the patients' insulin intake across all timeframes (mean difference = -0.123, 95% CI: -0.151 to -0.094, p < .001). However, no significant effect on glycated haemoglobin concentration was observed. CONCLUSION The findings of this review suggest that anti-CD3 monoclonal antibody treatment increases endogenous insulin production and improves the lifestyle of patients by reducing insulin dosage. Future studies should consider the limitations, including sample size, heterogeneity and duration of follow-up, to validate the generalizability of these findings further.
Collapse
Affiliation(s)
- Muhammad Talal Ashraf
- Department of Internal Medicine, Dow University of Health Sciences, Karachi, Pakistan
| | | | | | | | - Syed Hassan Ahmed
- Department of Internal Medicine, Dow University of Health Sciences, Karachi, Pakistan
| | | |
Collapse
|
|
7
|
Russell WE, Moore DJ, Herold KC. Response to Comment on Russell et al. Abatacept for Delay of Type 1 Diabetes Progression in Stage 1 Relatives at Risk: A Randomized, Double-Masked, Controlled Trial. Diabetes Care 2023;46:1005-1013. Diabetes Care 2023; 46:e210-e211. [PMID: 37890101 PMCID: PMC10620531 DOI: 10.2337/dci23-0050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Accepted: 08/01/2023] [Indexed: 10/29/2023]
Affiliation(s)
- William E. Russell
- Departments of Pediatrics and Cell & Developmental Biology, Vanderbilt University Medical Center, Nashville, TN
| | - Daniel J. Moore
- Departments of Pediatrics and Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN
| | | |
Collapse
|
|
8
|
Landstra CP, Nijhoff MF, Roelen DL, de Vries APJ, de Koning EJP. Diagnosis and treatment of allograft rejection in islet transplantation. Am J Transplant 2023; 23:1425-1433. [PMID: 37307954 DOI: 10.1016/j.ajt.2023.05.035] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 05/07/2023] [Indexed: 06/14/2023]
Abstract
Islet transplantation stabilizes glycemic control in patients with complicated diabetes mellitus. Rapid functional decline could be due to islet allograft rejection. However, there is no reliable method to assess rejection, and treatment protocols are absent. We aimed to characterize diagnostic features of islet allograft rejection and assess effectiveness of high-dose methylprednisolone treatment. Over a median follow-up of 61.8 months, 22% (9 of 41) of islet transplant recipients experienced 10 suspected rejection episodes (SREs). All first SREs occurred within 18 months after transplantation. Important features were unexplained hyperglycemia (all cases), unexplained C-peptide decrease (ΔC-peptide, 77.1% [-59.1% to -91.6%]; ΔC-peptide:glucose, -76.3% [-49.2% to -90.4%]), predisposing event (5 of 10 cases), and increased immunologic risk (5 of 10 cases). At 6 months post-SRE, patients who received protocolized methylprednisolone (n = 4) had significantly better islet function than untreated patients (n = 4), according to C-peptide (1.39 ± 0.59 vs 0.14 ± 0.19 nmol/L; P = .007), Igls score (good [4 of 4 cases] vs failure [3 of 4 cases] or marginal [1 of 4 cases]; P = .018) and β score (6.0 [6.0-6.0] vs 1.0 [0.0-3.5]; P = .013). SREs are prevalent among islet transplant recipients and are associated with loss of islet graft function. Timely treatment with high-dose methylprednisolone mitigates this loss. Unexplained hyperglycemia, unexpected C-peptide decrease, a predisposing event, and elevated immunologic risk are diagnostic indicators for SRE.
Collapse
Affiliation(s)
- Cyril P Landstra
- Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Michiel F Nijhoff
- Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands; Leiden Transplant Center, Leiden University Medical Center, Leiden, The Netherlands
| | - Dave L Roelen
- Leiden Transplant Center, Leiden University Medical Center, Leiden, The Netherlands; Department of Immunohematology, Leiden University Medical Center, Leiden, The Netherlands
| | - Aiko P J de Vries
- Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands; Leiden Transplant Center, Leiden University Medical Center, Leiden, The Netherlands
| | - Eelco J P de Koning
- Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands; Leiden Transplant Center, Leiden University Medical Center, Leiden, The Netherlands.
| |
Collapse
|
|
9
|
Song M, Fan X. Systemic Metabolism and Mitochondria in the Mechanism of Alzheimer's Disease: Finding Potential Therapeutic Targets. Int J Mol Sci 2023; 24:ijms24098398. [PMID: 37176104 PMCID: PMC10179273 DOI: 10.3390/ijms24098398] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 04/30/2023] [Accepted: 05/05/2023] [Indexed: 05/15/2023] Open
Abstract
Elderly people over the age of 65 are those most likely to experience Alzheimer's disease (AD), and aging and AD are associated with apparent metabolic alterations. Currently, there is no curative medication against AD and only several drugs have been approved by the FDA, but these drugs can only improve the symptoms of AD. Many preclinical and clinical trials have explored the impact of adjusting the whole-body and intracellular metabolism on the pathogenesis of AD. The most recent evidence suggests that mitochondria initiate an integrated stress response to environmental stress, which is beneficial for healthy aging and neuroprotection. There is also an increasing awareness of the differential risk and potential targeting strategies related to the metabolic level and microbiome. As the main participants in intracellular metabolism, mitochondrial bioenergetics, mitochondrial quality-control mechanisms, and mitochondria-linked inflammatory responses have been regarded as potential therapeutic targets for AD. This review summarizes and highlights these advances.
Collapse
Affiliation(s)
- Meiying Song
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Xiang Fan
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| |
Collapse
|
|
10
|
Misra S, Shukla AK. Teplizumab: type 1 diabetes mellitus preventable? Eur J Clin Pharmacol 2023; 79:609-616. [PMID: 37004543 DOI: 10.1007/s00228-023-03474-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 03/08/2023] [Indexed: 04/04/2023]
Abstract
Type 1 diabetes mellitus (T1DM) is an autoimmune condition driven by T lymphocytes that specifically declines the function of beta cells of pancreas. Immunological treatments aim to stop this decline in β-cell function thus preventing TIDM. Although TIDM occur at any age, it is one of the most common chronic disorders in children. T1DM accounts for 5 to 10% of all cases of diabetes amounting 21-42 million affected persons. Teplizumab is a novel drug recently approved by the US FDA for the treatment of T1DM. This drug reduces abnormal glucose tolerance who are at high risk for developing T1DM and have antibodies suggesting an immunological attack on their pancreas. A 14-day infusion of the drug prevents T cells' attack of the insulin-producing cells of the pancreas. Adverse events due to teplizumab reported so far mild and of limited duration. This review gives an overview of the preclinical and clinical research on teplizumab for their role in new-onset T1DM.
Collapse
Affiliation(s)
- Saurav Misra
- Department of Pharmacology, Kalpana Chawla Government Medical College, Karnal, Haryana, India.
| | - Ajay Kumar Shukla
- Department of Pharmacology, AIIMS Bhopal, Bhopal, Madhya Pradesh, India
| |
Collapse
|
|
11
|
Jing Z, Li Y, Ma Y, Zhang X, Liang X, Zhang X. Leverage biomaterials to modulate immunity for type 1 diabetes. Front Immunol 2022; 13:997287. [PMID: 36405706 PMCID: PMC9667795 DOI: 10.3389/fimmu.2022.997287] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 09/20/2022] [Indexed: 09/08/2024] Open
Abstract
The pathogeny of type 1 diabetes (T1D) is mainly provoked by the β-cell loss due to the autoimmune attack. Critically, autoreactive T cells firsthand attack β-cell in islet, that results in the deficiency of insulin in bloodstream and ultimately leads to hyperglycemia. Hence, modulating immunity to conserve residual β-cell is a desirable way to treat new-onset T1D. However, systemic immunosuppression makes patients at risk of organ damage, infection, even cancers. Biomaterials can be leveraged to achieve targeted immunomodulation, which can reduce the toxic side effects of immunosuppressants. In this review, we discuss the recent advances in harness of biomaterials to immunomodulate immunity for T1D. We investigate nanotechnology in targeting delivery of immunosuppressant, biological macromolecule for β-cell specific autoreactive T cell regulation. We also explore the biomaterials for developing vaccines and facilitate immunosuppressive cells to restore immune tolerance in pancreas.
Collapse
Affiliation(s)
- Zhangyan Jing
- Department of Pharmacology, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Yuan Li
- Department of Pharmacology, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Yumeng Ma
- Department of Pharmacology, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Xiaozhou Zhang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Key Laboratory of Stem Cell and Regenerative Tissue Engineering, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, China
| | - Xin Liang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Key Laboratory of Stem Cell and Regenerative Tissue Engineering, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, China
| | - Xudong Zhang
- Department of Pharmacology, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-sen University, Shenzhen, Guangdong, China
| |
Collapse
|
|
12
|
Abstract
First envisioned by early diabetes clinicians, a person-centred approach to care was an aspirational goal that aimed to match insulin therapy to each individual's unique requirements. In the 100 years since the discovery of insulin, this goal has evolved to include personalised approaches to type 1 diabetes diagnosis, treatment, prevention and prediction. These advances have been facilitated by the recognition of type 1 diabetes as an autoimmune disease and by advances in our understanding of diabetes pathophysiology, genetics and natural history, which have occurred in parallel with advancements in insulin delivery, glucose monitoring and tools for self-management. In this review, we discuss how these personalised approaches have improved diabetes care and how improved understanding of pathogenesis and human biology might inform precision medicine in the future.
Collapse
Affiliation(s)
- Alice L J Carr
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
| | - Carmella Evans-Molina
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA
- Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
- Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA
| | - Richard A Oram
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
| |
Collapse
|
|
13
|
Ludvigsson J. Glutamic acid decarboxylase immunotherapy for type 1 diabetes. Curr Opin Endocrinol Diabetes Obes 2022; 29:361-369. [PMID: 35776501 DOI: 10.1097/med.0000000000000748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
PURPOSE OF REVIEW To describe recent development of an autoantigen (GAD) treatment towards well tolerated and efficacious precision medicine in type 1 diabetes. RECENT FINDINGS Although subcutaneous GAD-alum treatment failed to reach primary endpoint in a phase III trial, metanalyses showed a 97% probability of efficacy, and clear efficacy in patients carrying Hyman Leucoycte Antigen (HLA) DR3DQ2. Efforts have been made to improve efficacy by trying combination therapies with vitamin D + Ibuprofen resp vitamin D + Etanercept (TNF-α inhibition), without any breakthrough until the administration of GAD-alum was changed from subcutaneous to intralymphatic. With a very small dose of GAD-alum (4 μg) given into an inguinal lymph three times with 1 month interval, the efficacy in patients with HLADR3DQ2 has been impressive, with significantly better beta cell preservation than patients who got placebo in a double-blind randomized trial, and clinical efficacy with more patients in partial remission (IDAA1c < 9) and larger proportion of patients with CGM-measured blood glucose Time In Range (TIR), significantly correlated to the C-peptide values. The treatment has been easy for patients and healthcare without treatment-related risk or adverse events. SUMMARY Intralymphatic GAD-alum treatment in type 1 diabetes patients carrying HLA DR3DQ2 seems to be an attractive immune intervention.
Collapse
Affiliation(s)
- Johnny Ludvigsson
- Crown Princess Victoria Children's Hospital and Division of Pediatrics, Departmentt of Biomedical and Clinical Sciences, Linköping University, Sweden
| |
Collapse
|
|
14
|
Austad SN, Ballinger S, Buford TW, Carter CS, Smith DL, Darley-Usmar V, Zhang J. Targeting whole body metabolism and mitochondrial bioenergetics in the drug development for Alzheimer's disease. Acta Pharm Sin B 2022; 12:511-531. [PMID: 35256932 PMCID: PMC8897048 DOI: 10.1016/j.apsb.2021.06.014] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/26/2021] [Accepted: 06/16/2021] [Indexed: 02/07/2023] Open
Abstract
Aging is by far the most prominent risk factor for Alzheimer's disease (AD), and both aging and AD are associated with apparent metabolic alterations. As developing effective therapeutic interventions to treat AD is clearly in urgent need, the impact of modulating whole-body and intracellular metabolism in preclinical models and in human patients, on disease pathogenesis, have been explored. There is also an increasing awareness of differential risk and potential targeting strategies related to biological sex, microbiome, and circadian regulation. As a major part of intracellular metabolism, mitochondrial bioenergetics, mitochondrial quality-control mechanisms, and mitochondria-linked inflammatory responses have been considered for AD therapeutic interventions. This review summarizes and highlights these efforts.
Collapse
Key Words
- ACE2, angiotensin I converting enzyme (peptidyl-dipeptidase A) 2
- AD, Alzheimer's disease
- ADP, adenosine diphosphate
- ADRD, AD-related dementias
- Aβ, amyloid β
- CSF, cerebrospinal fluid
- Circadian regulation
- DAMPs
- DAMPs, damage-associated molecular patterns
- Diabetes
- ER, estrogen receptor
- ETC, electron transport chain
- FCCP, trifluoromethoxy carbonylcyanide phenylhydrazone
- FPR-1, formyl peptide receptor 1
- GIP, glucose-dependent insulinotropic polypeptide
- GLP-1, glucagon-like peptide-1
- HBP, hexoamine biosynthesis pathway
- HTRA, high temperature requirement A
- Hexokinase biosynthesis pathway
- I3A, indole-3-carboxaldehyde
- IRF-3, interferon regulatory factor 3
- LC3, microtubule associated protein light chain 3
- LPS, lipopolysaccharide
- LRR, leucine-rich repeat
- MAVS, mitochondrial anti-viral signaling
- MCI, mild cognitive impairment
- MRI, magnetic resonance imaging
- MRS, magnetic resonance spectroscopy
- Mdivi-1, mitochondrial division inhibitor 1
- Microbiome
- Mitochondrial DNA
- Mitochondrial electron transport chain
- Mitochondrial quality control
- NLRP3, leucine-rich repeat (LRR)-containing protein (NLR)-like receptor family pyrin domain containing 3
- NOD, nucleotide-binding oligomerization domain
- NeuN, neuronal nuclear protein
- PET, fluorodeoxyglucose (FDG)-positron emission tomography
- PKA, protein kinase A
- POLβ, the base-excision repair enzyme DNA polymerase β
- ROS, reactive oxygen species
- Reactive species
- SAMP8, senescence-accelerated mice
- SCFAs, short-chain fatty acids
- SIRT3, NAD-dependent deacetylase sirtuin-3
- STING, stimulator of interferon genes
- STZ, streptozotocin
- SkQ1, plastoquinonyldecyltriphenylphosphonium
- T2D, type 2 diabetes
- TCA, Tricarboxylic acid
- TLR9, toll-like receptor 9
- TMAO, trimethylamine N-oxide
- TP, tricyclic pyrone
- TRF, time-restricted feeding
- cAMP, cyclic adenosine monophosphate
- cGAS, cyclic GMP/AMP synthase
- hAPP, human amyloid precursor protein
- hPREP, human presequence protease
- i.p., intraperitoneal
- mTOR, mechanistic target of rapamycin
- mtDNA, mitochondrial DNA
- αkG, alpha-ketoglutarate
Collapse
Affiliation(s)
- Steven N. Austad
- Department of Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Scott Ballinger
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Thomas W. Buford
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Christy S. Carter
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Daniel L. Smith
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Victor Darley-Usmar
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Jianhua Zhang
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| |
Collapse
|
|
15
|
Björklund A, Hals IK, Grill V, Ludvigsson J. Latent Autoimmune Diabetes in Adults: Background, Safety and Feasibility of an Ongoing Pilot Study With Intra-Lymphatic Injections of GAD-Alum and Oral Vitamin D. Front Endocrinol (Lausanne) 2022; 13:926021. [PMID: 35923626 PMCID: PMC9339700 DOI: 10.3389/fendo.2022.926021] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 06/08/2022] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Latent Autoimmune Diabetes in Adults (LADA) constitutes around 10% of all diabetes. Many LADA patients gradually lose their insulin secretion and progress to insulin dependency. In a recent trial BALAD (Behandling Av LADa) early insulin treatment compared with sitagliptin failed to preserve insulin secretion, which deteriorated in individuals displaying high levels of antibodies to GAD (GADA). These findings prompted us to evaluate a treatment that directly affects autoimmunity. Intra-lymphatic GAD-alum treatment has shown encouraging results in Type 1 diabetes patients. We therefore tested the feasibility of such therapy in LADA-patients (the GADinLADA pilot study). MATERIAL AND METHODS Fourteen GADA-positive (>190 RU/ml), insulin-independent patients 30-70 years old, with LADA diagnosed within < 36 months were included in an open-label feasibility trial. They received an intra-nodal injection of 4 μg GAD-alum at Day 1, 30 and 60 plus oral Vitamin D 2000 U/d from screening 30 days before (Day -30) for 4 months if the vitamin D serum levels were below 100 nmol/L (40 ng/ml). Primary objective is to evaluate safety and feasibility. Mixed Meal Tolerance Test and i.v. Glucagon Stimulation Test at baseline and after 5 and 12 months are used for estimation of beta cell function. Results will be compared with those of the recent BALAD study with comparable patient population. Immunological response is followed. RESULTS Preliminary results show feasibility and safety, with almost stable beta cell function and metabolic control during follow-up so far (5 months). CONCLUSIONS Intra-lymphatic GAD-alum treatment is an option to preserve beta cell function in LADA-patients. An ongoing trial in 14 LADA-patients show feasibility and safety. Clinical and immunological responses will determine how to proceed with future trials.
Collapse
Affiliation(s)
- Anneli Björklund
- Department of Molecular medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Endocrine and Diabetes Unit, Karolinska University Hospital, Stockholm, Sweden
- Diabetes Center, Academic Specialist Center, Region Stockholm, Stockholm, Sweden
| | - Ingrid K. Hals
- Department of Endocrinology, Clinic of Medicine, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
- Nord-Trondelag Hospital Trust, Levanger, Norway
| | - Valdemar Grill
- Department of Endocrinology, Clinic of Medicine, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Johnny Ludvigsson
- Division of Pediatrics, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
- Crown Princess Victoria Children´s Hospital, Linköping, Sweden
- *Correspondence: Johnny Ludvigsson,
| |
Collapse
|
|
16
|
Bower JAJ, O'Flynn L, Kakad R, Aldulaimi D. Effect of inflammatory bowel disease treatments on patients with diabetes mellitus. World J Diabetes 2021; 12:1248-1254. [PMID: 34512890 PMCID: PMC8394226 DOI: 10.4239/wjd.v12.i8.1248] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 04/13/2021] [Accepted: 07/12/2021] [Indexed: 02/06/2023] Open
Abstract
As medical care progresses and the number of patients with chronic conditions increases there is the inevitable challenge of managing patients with multiple co-morbidities. Inflammatory bowel disease (IBD) is an umbrella term for are inflammatory conditions affecting the gastrointestinal tract, the two most common forms being Ulcerative Colitis and Crohn’s disease. These diseases, usually diagnosed in young adults, exhibit a relapsing and remitting course and usually require long-term treatment. IBD can be treated with a number of topical and systemic treatments. We conducted a review of the current published evidence for the effects these medications can have on diabetes mellitus (DM) and glycaemic control. Searches were conducted on medline and embase with a timeframe from 1947 (the date from which studies on embase are recorded) to November 2020. Suitable publications were selected and reviewed. Current evidence of the impact of aminosalicylates, corticosteroids, thiopurines, and biologic agents was reviewed. Though there was limited evidence for certain agents, IBD medications have been shown to have an effect of DM and these effects should be considered in managing patients with dual pathologies. The effects of steroids on blood sugar control is well documented, but consideration of other agents is also important. In patients requiring steroids for Ulcerative Colitis, locally acting steroid agents delivered rectally may be preferred to minimise side effects in those with distal bowel Ulcerative Colitis. A switch to other agents should be considered as soon as possible in people with diabetes to limit the impact on glycaemic control. 5-aminosalicylates appear to play a role in the reduction of hemoglobin A1c (HbA1c), although the literature suggests these may be falsely low readings. Consequently, monitoring of people with diabetes on these agents may require daily monitoring of capillary blood sugars rather than relying simply on HbA1c; for example fructosamine performed 3-6 monthly, although this risks missing the rise in readings. There is only limited evidence of the effects of thiopurines on diabetes and further investigation is needed into the possible relationship between them. However, given the current available evidence it may be preferable to commence patients with diabetes on thiopurines as soon as possible, whilst also monitoring for side effects such as pancreatitis. There appears to be more evidence supporting a link between tumor necrosis factor-α inhibitors and DM. Both infliximab and adalimumab have evidence suggesting that both can cause reduced blood sugar levels. Further studies on the effects of the various biological agents mentioned are required alongside any novel biologic therapy and the impact of dual biologic therapy in the future.
Collapse
Affiliation(s)
- Joshua Ashley Jack Bower
- Department of Gastroenterology, South Warwickshire Foundation Trust, Warwick CV34 5BW, United Kingdom
| | - Lauren O'Flynn
- Department of Gastroenterology, South Warwickshire Foundation Trust, Warwick CV34 5BW, United Kingdom
| | - Rakhi Kakad
- Department of Endocrinology, South Warwickshire Foundation Trust, Warwick CV34 5BW, United Kingdom
| | - David Aldulaimi
- Department of Gastroenterology, South Warwickshire Foundation Trust, Warwick CV34 5BW, United Kingdom
| |
Collapse
|
|
17
|
Rispoli MG, Ferri L, Ajdinaj P, Falzano V, Di Muzio A. Guillain-Barré syndrome and myasthenia gravis in the context of autoimmune polyendocrine syndrome type III. Neurol Sci 2021; 42:4789-4792. [PMID: 34331156 DOI: 10.1007/s10072-021-05517-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Accepted: 07/18/2021] [Indexed: 10/20/2022]
Affiliation(s)
- Marianna Gabriella Rispoli
- Department of Neuroscience, Imaging and Clinical Sciences, G. D'Annunzio University, SS Annunziata Hospital, Via dei Vestini, 66100, Chieti, Abruzzo, Italy. .,Center for Neuromuscular Diseases, "SS Annunziata" Hospital, Chieti, Abruzzo, Italy.
| | - Laura Ferri
- Department of Neuroscience, Imaging and Clinical Sciences, G. D'Annunzio University, SS Annunziata Hospital, Via dei Vestini, 66100, Chieti, Abruzzo, Italy.,Center for Neuromuscular Diseases, "SS Annunziata" Hospital, Chieti, Abruzzo, Italy
| | - Paola Ajdinaj
- Department of Neuroscience, Imaging and Clinical Sciences, G. D'Annunzio University, SS Annunziata Hospital, Via dei Vestini, 66100, Chieti, Abruzzo, Italy.,Center for Neuromuscular Diseases, "SS Annunziata" Hospital, Chieti, Abruzzo, Italy
| | - Valeriana Falzano
- Endocrinology Unit, "SS Annunziata" Hospital, Chieti, Abruzzo, Italy
| | - Antonio Di Muzio
- Center for Neuromuscular Diseases, "SS Annunziata" Hospital, Chieti, Abruzzo, Italy.,Department of Neurology, SS Annunziata Hospital, Chieti, Italy
| |
Collapse
|
|
18
|
Wong TWC, Wong MYS, But WMB. Features of partial remission in children with type 1 diabetes using the insulin dose-adjusted A1c definition and risk factors associated with nonremission. Ann Pediatr Endocrinol Metab 2021; 26:118-125. [PMID: 34218633 PMCID: PMC8255863 DOI: 10.6065/apem.2040202.101] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 12/17/2020] [Indexed: 12/15/2022] Open
Abstract
PURPOSE We sought to evaluate features of partial remission (PR) in children with type 1 diabetes mellitus (T1DM) using the insulin-dose adjusted A1c (IDAA1c) definition and to identify risk factors associated with nonremission. METHODS Medical records of patients with newly diagnosed T1DM between January 1, 2008, and June 30, 2018, were retrospectively reviewed. Hemoglobin A1c (HbA1c) readings and insulin total daily doses (TDDs) of each patient at each follow-up visit were obtained with IDAA1c values calculated. PR was defined as an IDAA1c score of 9 points or less within 6 months of diagnosis. The trends of HbA1c and TDD within 2 years after diagnosis were compared between remitters and nonremitters. Factors that may predict the occurrence of PR were studied, with their relative risks of nonremission calculated. RESULTS PR occurred in 26 patients (45.6%), including 8 girls and 18 boys, with a median duration of 8 months. The frequency of remission in male patients was significantly higher (P=0.002) and the relative risk of female sex with nonremission was 2.20 (95% confidence interval [CI], 1.24-3.91), which remained significant when adjusted by multivariate regression modeling. The initial HbA1c level at diagnosis was also significantly higher in the nonremission group (P=0.029), with a relative risk of 1.12 (95% CI, 1.01-1.25). Both HbA1c (P=0.012) and TDD (P=0.006) were significantly lower within 2 years after diagnosis among remitters than in nonremitters. TDD was significantly lower in male patients (P=0.029) during the same period, while there was no significant difference in HbA1c level between male and female patients (P=0.163). CONCLUSION Both the initial HbA1c level at diagnosis and sex were factors associated with the occurrence of PR. Female sex was an independent risk factor of nonremission, likely resulting from a higher insulin requirement in female T1DM patients.
Collapse
Affiliation(s)
- Tsz Wai Catherine Wong
- Department of Paediatrics, Queen Elizabeth Hospital, Jordan, Hong Kong,Address for correspondence:
Tsz Wai Catherine Wong
Department of Paediatrics, Queen
Elizabeth Hospital, 30 Gascoigne
Road, Jordan, Hong Kong
| | | | - Wai Man Betty But
- Department of Paediatrics, Queen Elizabeth Hospital, Jordan, Hong Kong
| |
Collapse
|
|
19
|
Pearson JA, McKinney EF, Walker LSK. 100 years post-insulin: immunotherapy as the next frontier in type 1 diabetes. IMMUNOTHERAPY ADVANCES 2021; 1:ltab024. [PMID: 35156097 PMCID: PMC8826223 DOI: 10.1093/immadv/ltab024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 11/15/2021] [Accepted: 11/20/2021] [Indexed: 02/03/2023] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease characterised by T cell-mediated destruction of the insulin-producing β cells in the pancreas. Similar to other autoimmune diseases, the incidence of T1D is increasing globally. The discovery of insulin 100 years ago dramatically changed the outlook for people with T1D, preventing this from being a fatal condition. As we celebrate the centenary of this milestone, therapeutic options for T1D are once more at a turning point. Years of effort directed at developing immunotherapies are finally starting to pay off, with signs of progress in new onset and even preventative settings. Here, we review a selection of immunotherapies that have shown promise in preserving β cell function and highlight future considerations for immunotherapy in the T1D setting.
Collapse
Affiliation(s)
- James A Pearson
- Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, Wales, UK
| | - Eoin F McKinney
- Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge, England, UK
- Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, England, UK
- Cambridge Centre for Artificial Intelligence in Medicine, University of Cambridge, Cambridge, England, UK
| | - Lucy S K Walker
- Division of Infection and Immunity, Institute or Immunity and Transplantation, University College London, Royal Free Campus, London, UK
| |
Collapse
|
|
20
|
Chevallier E, Jouve T, Rostaing L, Malvezzi P, Noble J. pre-existing diabetes and PTDM in kidney transplant recipients: how to handle immunosuppression. Expert Rev Clin Pharmacol 2020; 14:55-66. [PMID: 33196346 DOI: 10.1080/17512433.2021.1851596] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
INTRODUCTION Preexisting diabetes (PD) and post-transplant diabetes mellitus (PTDM) are common and severe comorbidities posttransplantation. The immunosuppressive regimens are modifiable risk factors. AREAS COVERED We reviewed Pubmed and Cochrane database and we summarize the mechanisms and impacts of available immunosuppressive treatments on the risk of PD and PTDM. We also assess the possible management of these drugs to improve glycemic parameters while considering risks inherent in transplantation. EXPERT OPINION PD i) increases the risk of sepsis, ii) is an independent risk factor for infection-related mortality, and iii) increases acute rejection risk. Regarding PTDM development i) immunosuppressive strategies without corticosteroids significantly reduce the risk but the price may be a higher incidence of rejection; ii) minimization or rapid withdrawal of steroids are two valuable approaches; iii) the diabetogenic role of calcineurin inhibitors(CNIs) is also well-described and is more important for tacrolimus than for cyclosporine. Reducing tacrolimus-exposure may improve glycemic parameters but also has a higher risk of rejection. PTDM risk is higher in patients that receive sirolimus compared to mycophenolate mofetil. Finally, conversion from CNIs to belatacept may offer the best benefits to PTDM-recipients in terms of glycemic parameters, graft and patient-outcomes.
Collapse
Affiliation(s)
- Eloi Chevallier
- Service De Néphrologie, Hémodialyse, Aphérèses Et Transplantation Rénale, CHU Grenoble-Alpes , Grenoble, France
| | - Thomas Jouve
- Service De Néphrologie, Hémodialyse, Aphérèses Et Transplantation Rénale, CHU Grenoble-Alpes , Grenoble, France.,Université Grenoble Alpes , Grenoble, France
| | - Lionel Rostaing
- Service De Néphrologie, Hémodialyse, Aphérèses Et Transplantation Rénale, CHU Grenoble-Alpes , Grenoble, France.,Université Grenoble Alpes , Grenoble, France
| | - Paolo Malvezzi
- Service De Néphrologie, Hémodialyse, Aphérèses Et Transplantation Rénale, CHU Grenoble-Alpes , Grenoble, France
| | - Johan Noble
- Service De Néphrologie, Hémodialyse, Aphérèses Et Transplantation Rénale, CHU Grenoble-Alpes , Grenoble, France
| |
Collapse
|
|
21
|
Luo YL, Liang LF, Gan YJ, Liu J, Zhang Y, Fan YN, Zhao G, Czarna A, Lu ZD, Du XJ, Shen S, Xu CF, Lian ZX, Wang J. An All-in-One Nanomedicine Consisting of CRISPR-Cas9 and an Autoantigen Peptide for Restoring Specific Immune Tolerance. ACS APPLIED MATERIALS & INTERFACES 2020; 12:48259-48271. [PMID: 33070614 DOI: 10.1021/acsami.0c10885] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Nanotechnology has shown great promise in treating diverse diseases. However, developing nanomedicines that can cure autoimmune diseases without causing systemic immunosuppression is still quite challenging. Herein, we propose an all-in-one nanomedicine comprising an autoantigen peptide and CRISPR-Cas9 to restore specific immune tolerance by engineering dendritic cells (DCs) into a tolerogenic phenotype, which can expand autoantigen-specific regulatory T (Treg) cells. In brief, we utilized cationic lipid-assisted poly(ethylene glycol)-b-poly(lactide-co-glycolide) (PEG-PLGA) nanoparticles to simultaneously encapsulate an autoimmune diabetes-relevant peptide (2.5mi), a CRISPR-Cas9 plasmid (pCas9), and three guide RNAs (gRNAs) targeting costimulatory molecules (CD80, CD86, and CD40). We demonstrated that the all-in-one nanomedicine was able to effectively codeliver these components into DCs, followed by simultaneous disruption of the three costimulatory molecules and presentation of the 2.5mi peptide on the genome-edited DCs. The resulting tolerogenic DCs triggered the generation and expansion of autoantigen-specific Treg cells by presenting the 2.5mi peptide to CD4+ T cells in the absence of costimulatory signals. Using autoimmune type 1 diabetes (T1D) as a typical disease model, we demonstrated that our nanomedicine prevented autoimmunity to islet components and inhibited T1D development. Our all-in-one nanomedicine achieved codelivery of CRISPR-Cas9 and the peptide to DCs and could be easily applied to other autoimmune diseases by substitution of different autoantigen peptides.
Collapse
Affiliation(s)
- Ying-Li Luo
- Guangzhou First People's Hospital, School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou 510006, P. R. China
| | - Li-Fang Liang
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, P. R. China
| | - Yun-Jiu Gan
- Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei 230027, P. R. China
| | - Jing Liu
- Guangzhou First People's Hospital, School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou 510006, P. R. China
| | - Yue Zhang
- Guangzhou First People's Hospital, School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou 510006, P. R. China
| | - Ya-Nan Fan
- Guangzhou First People's Hospital, School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou 510006, P. R. China
| | - Gui Zhao
- Guangzhou First People's Hospital, School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou 510006, P. R. China
| | - Anna Czarna
- Institutes for Life Sciences, School of Medicine, South China University of Technology, Guangzhou 510006, P. R. China
| | - Zi-Dong Lu
- Institutes for Life Sciences, School of Medicine, South China University of Technology, Guangzhou 510006, P. R. China
| | - Xiao-Jiao Du
- Institutes for Life Sciences, School of Medicine, South China University of Technology, Guangzhou 510006, P. R. China
- Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, South China University of Technology, Guangzhou 510006, P. R. China
| | - Song Shen
- Guangzhou First People's Hospital, School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou 510006, P. R. China
| | - Cong-Fei Xu
- Guangzhou First People's Hospital, School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou 510006, P. R. China
| | - Zhe-Xiong Lian
- Institutes for Life Sciences, School of Medicine, South China University of Technology, Guangzhou 510006, P. R. China
| | - Jun Wang
- Guangzhou First People's Hospital, School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou 510006, P. R. China
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou 510006, P. R. China
- Key Laboratory of Biomedical Engineering of Guangdong Province, and Innovation Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou 510006, P. R. China
- Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, P. R. China
- Research Institute for Food Nutrition and Human Health, Guangzhou 510641, P. R. China
| |
Collapse
|
|
22
|
Beik P, Ciesielska M, Kucza M, Kurczewska A, Kuźmińska J, Maćkowiak B, Niechciał E. Prevention of Type 1 Diabetes: Past Experiences and Future Opportunities. J Clin Med 2020; 9:E2805. [PMID: 32872668 PMCID: PMC7563637 DOI: 10.3390/jcm9092805] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 08/14/2020] [Accepted: 08/28/2020] [Indexed: 12/11/2022] Open
Abstract
Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing beta-cells in the pancreas, caused by the interplay of genetic and environmental factors. Despite the introduction of advanced technologies for diabetes management, most patients fail to achieve target glycemic control, and T1D still has a high burden of long-term end-organ complications. Over several decades, multiple clinical trials have attempted to find prevention for T1D in at-risk individuals or to stabilize, ultimately reverse, the disease in those with T1D. To date, T1D remains yet incurable condition; however, recently improved understanding of the natural history of the disease may lead to new strategies to preserve or improve beta-cell function in those at increased risk and T1D patients. This publication aims to provide an overview of past experiences and recent findings in the prevention of T1D.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Elżbieta Niechciał
- Department of Pediatric Diabetes and Obesity, Poznan University of Medical Sciences, Szpitalna Street 27/33, 60-572 Poznan, Poland; (P.B.); (M.C.); (M.K.); (A.K.); (J.K.); (B.M.)
| |
Collapse
|
|
23
|
Ferber C, Mao CS, Yee JK. Type 1 Diabetes in Youth and Technology-Based Advances in Management. Adv Pediatr 2020; 67:73-91. [PMID: 32591065 DOI: 10.1016/j.yapd.2020.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Affiliation(s)
- Christopher Ferber
- Department of Pediatrics, Harbor-UCLA Medical Center, 1000 West Carson Street, Harbor Box 446, Torrance, CA 90509, USA
| | - Catherine S Mao
- Division of Endocrinology, Department of Pediatrics, David Geffen School of Medicine at UCLA, Harbor-UCLA Medical Center, 1000 West Carson Street, Harbor Box 446, Torrance, CA 90509, USA; The Lundquist Institute of Biomedical Innvoation at Harbor-UCLA, 1124 West Carson Street, Torrance, CA 90502, USA
| | - Jennifer K Yee
- Division of Endocrinology, Department of Pediatrics, David Geffen School of Medicine at UCLA, Harbor-UCLA Medical Center, 1000 West Carson Street, Harbor Box 446, Torrance, CA 90509, USA; The Lundquist Institute of Biomedical Innvoation at Harbor-UCLA, 1124 West Carson Street, Torrance, CA 90502, USA.
| |
Collapse
|
|
24
|
Haller MJ, Long SA, Blanchfield JL, Schatz DA, Skyler JS, Krischer JP, Bundy BN, Geyer SM, Warnock MV, Miller JL, Atkinson MA, Becker DJ, Baidal DA, DiMeglio LA, Gitelman SE, Goland R, Gottlieb PA, Herold KC, Marks JB, Moran A, Rodriguez H, Russell WE, Wilson DM, Greenbaum CJ. Low-Dose Anti-Thymocyte Globulin Preserves C-Peptide, Reduces HbA 1c, and Increases Regulatory to Conventional T-Cell Ratios in New-Onset Type 1 Diabetes: Two-Year Clinical Trial Data. Diabetes 2019; 68:1267-1276. [PMID: 30967424 PMCID: PMC6610026 DOI: 10.2337/db19-0057] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Accepted: 03/23/2019] [Indexed: 12/19/2022]
Abstract
A three-arm, randomized, double-masked, placebo-controlled phase 2b trial performed by the Type 1 Diabetes TrialNet Study Group previously demonstrated that low-dose anti-thymocyte globulin (ATG) (2.5 mg/kg) preserved β-cell function and reduced HbA1c for 1 year in new-onset type 1 diabetes. Subjects (N = 89) were randomized to 1) ATG and pegylated granulocyte colony-stimulating factor (GCSF), 2) ATG alone, or 3) placebo. Herein, we report 2-year area under the curve (AUC) C-peptide and HbA1c, prespecified secondary end points, and potential immunologic correlates. The 2-year mean mixed-meal tolerance test-stimulated AUC C-peptide, analyzed by ANCOVA adjusting for baseline C-peptide, age, and sex (n = 82) with significance defined as one-sided P < 0.025, was significantly higher in subjects treated with ATG versus placebo (P = 0.00005) but not ATG/GCSF versus placebo (P = 0.032). HbA1c was significantly reduced at 2 years in subjects treated with ATG (P = 0.011) and ATG/GCSF (P = 0.022) versus placebo. Flow cytometry analyses demonstrated reduced circulating CD4:CD8 ratio, increased regulatory T-cell:conventional CD4 T-cell ratios, and increased PD-1+CD4+ T cells following low-dose ATG and ATG/GCSF. Low-dose ATG partially preserved β-cell function and reduced HbA1c 2 years after therapy in new-onset type 1 diabetes. Future studies should determine whether low-dose ATG might prevent or delay the onset of type 1 diabetes.
Collapse
Affiliation(s)
| | | | | | | | - Jay S Skyler
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
| | | | | | | | | | | | | | - Dorothy J Becker
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
- University of Pittsburgh, Pittsburgh, PA
| | - David A Baidal
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
| | | | | | | | - Peter A Gottlieb
- University of Colorado Barbara Davis Center for Childhood Diabetes, Aurora, CO
| | | | - Jennifer B Marks
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
| | | | | | | | | | | | | |
Collapse
|
|
25
|
Mbongue JC, Rawson J, Garcia PA, Gonzalez N, Cobb J, Kandeel F, Ferreri K, Husseiny MI. Reversal of New Onset Type 1 Diabetes by Oral Salmonella-Based Combination Therapy and Mediated by Regulatory T-Cells in NOD Mice. Front Immunol 2019; 10:320. [PMID: 30863412 PMCID: PMC6400227 DOI: 10.3389/fimmu.2019.00320] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 02/07/2019] [Indexed: 12/27/2022] Open
Abstract
Autoimmune diseases such as type 1 diabetes (T1D) involve the loss of regulatory mechanisms resulting in increased tissue-specific cytotoxicity. The result is destruction of pancreatic insulin-producing β-cells and loss of glucose homeostasis. We are developing a novel oral vaccine using live attenuated Salmonella to deliver TGFβ, IL10, and the diabetic autoantigen preproinsulin combined with low-doses of anti-CD3 mAb. Here we show that oral administration of Salmonella-based anti-CD3 mAb combined therapy reverses new-onset T1D in non-obese diabetic (NOD) mice. The therapeutic effect of the combined therapy was associated with induction of immune suppressive CD4+CD25+Foxp3+ Treg and CD4+CD49b+LAG3+ Tr1 cells. In adoptive transfer experiments, adding or depleting Treg or Tr1 cells indicated that both are important for preventing diabetes in combined therapy-treated mice, but that Tr1 cells may have a more central role. Furthermore, induced Tr1 cells were found to be antigen-specific responding to peptide stimulation by secreting tolerance inducing IL10. These preclinical data demonstrate a role for Treg and Tr1 cells in combined therapy-mediated induction of tolerance in NOD mice. These results also demonstrate the potential of oral Salmonella-based combined therapy in the treatment of early T1D.
Collapse
Affiliation(s)
- Jacques C Mbongue
- Department of Translational Research & Cellular Therapeutics, Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, United States
| | - Jeffrey Rawson
- Department of Translational Research & Cellular Therapeutics, Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, United States
| | - Pablo A Garcia
- Department of Translational Research & Cellular Therapeutics, Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, United States
| | - Nelson Gonzalez
- Department of Translational Research & Cellular Therapeutics, Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, United States
| | - Jacob Cobb
- Department of Translational Research & Cellular Therapeutics, Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, United States
| | - Fouad Kandeel
- Department of Translational Research & Cellular Therapeutics, Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, United States
| | - Kevin Ferreri
- Department of Translational Research & Cellular Therapeutics, Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, United States
| | - Mohamed I Husseiny
- Department of Translational Research & Cellular Therapeutics, Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, United States.,Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| |
Collapse
|
|
26
|
Allam MM, Elzawawy HTH. Induction of remission in autoimmune polyglandular syndrome type three (APS III): An old drug with new perspectives. Clin Case Rep 2018; 6:2178-2184. [PMID: 30455916 PMCID: PMC6230650 DOI: 10.1002/ccr3.1827] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 06/06/2018] [Accepted: 08/30/2018] [Indexed: 01/06/2023] Open
Abstract
The autoimmune polyglandular syndrome is a sequential chain of autoimmune events. Whenever diagnosed, the clinician's target should be induction of remission and if possible hindering its progression especially if associated with refractory vitiligo, resistant Grave's, or unexplained hyperglycemia in T1DM. Azathioprine could be used for induction of remission in autoimmune polyglandular syndrome type three especially with vitiligo and autoimmune thyroiditis.
Collapse
Affiliation(s)
- Magdy Mohamed Allam
- Internal Medicine DepartmentAlexandria University Student Hospital (AUSH)AlexandriaEgypt
| | | |
Collapse
|
|
27
|
Haller MJ, Schatz DA, Skyler JS, Krischer JP, Bundy BN, Miller JL, Atkinson MA, Becker DJ, Baidal D, DiMeglio LA, Gitelman SE, Goland R, Gottlieb PA, Herold KC, Marks JB, Moran A, Rodriguez H, Russell W, Wilson DM, Greenbaum CJ, Greenbaum C, Atkinson M, Baidal D, Battaglia M, Becker D, Bingley P, Bosi E, Buckner J, Clements M, Colman P, DiMeglio L, Evans-Molina C, Gitelman S, Goland R, Gottlieb P, Herold K, Knip M, Krischer J, Lernmark A, Moore W, Moran A, Muir A, Palmer J, Peakman M, Philipson L, Raskin P, Redondo M, Rodriguez H, Russell W, Spain L, Schatz D, Sosenko J, Wherrett D, Wilson D, Winter W, Ziegler A, Anderson M, Antinozzi P, Benoist C, Blum J, Bourcier K, Chase P, Clare-Salzler M, Clynes R, Cowie C, Eisenbarth G, Fathman C, Grave G, Harrison L, Hering B, Insel R, Jordan S, Kaufman F, Kay T, Kenyon N, Klines R, Lachin J, Leschek E, Mahon J, Marks J, Monzavi R, Nanto-Salonen K, Nepom G, Orban T, Parkman R, Pescovitz M, Peyman J, Pugliese A, Ridge J, Roep B, Roncarolo M, Savage P, Simell O, Sherwin R, Siegelman M, Skyler J, Steck A, Thomas J, Trucco M, Wagner J, et alHaller MJ, Schatz DA, Skyler JS, Krischer JP, Bundy BN, Miller JL, Atkinson MA, Becker DJ, Baidal D, DiMeglio LA, Gitelman SE, Goland R, Gottlieb PA, Herold KC, Marks JB, Moran A, Rodriguez H, Russell W, Wilson DM, Greenbaum CJ, Greenbaum C, Atkinson M, Baidal D, Battaglia M, Becker D, Bingley P, Bosi E, Buckner J, Clements M, Colman P, DiMeglio L, Evans-Molina C, Gitelman S, Goland R, Gottlieb P, Herold K, Knip M, Krischer J, Lernmark A, Moore W, Moran A, Muir A, Palmer J, Peakman M, Philipson L, Raskin P, Redondo M, Rodriguez H, Russell W, Spain L, Schatz D, Sosenko J, Wherrett D, Wilson D, Winter W, Ziegler A, Anderson M, Antinozzi P, Benoist C, Blum J, Bourcier K, Chase P, Clare-Salzler M, Clynes R, Cowie C, Eisenbarth G, Fathman C, Grave G, Harrison L, Hering B, Insel R, Jordan S, Kaufman F, Kay T, Kenyon N, Klines R, Lachin J, Leschek E, Mahon J, Marks J, Monzavi R, Nanto-Salonen K, Nepom G, Orban T, Parkman R, Pescovitz M, Peyman J, Pugliese A, Ridge J, Roep B, Roncarolo M, Savage P, Simell O, Sherwin R, Siegelman M, Skyler J, Steck A, Thomas J, Trucco M, Wagner J, Bourcier K, Greenbaum CJ, Krischer JP, Leschek E, Rafkin L, Spain L, Cowie C, Foulkes M, Insel R, Krause-Steinrauf H, Lachin JM, Malozowski S, Peyman J, Ridge J, Savage P, Skyler JS, Zafonte SJ, Greenbaum CJ, Rafkin L, Sosenko JM, Skyler JS, Kenyon NS, Santiago I, Krischer JP, Bundy B, Abbondondolo M, Adams T, Amado D, Asif I, Boonstra M, Boulware D, Bundy B, Burroughs C, Cuthbertson D, Eberhard C, Fiske S, Ford J, Garmeson J, Guillette H, Geyer S, Hays B, Henderson C, Henry M, Heyman K, Hsiao B, Karges C, Kinderman A, Lane L, Leinbach A, Liu S, Lloyd J, Malloy J, Maddox K, Martin J, Miller J, Moore M, Muller S, Nguyen T, O’Donnell R, Parker M, Pereyra M, Reed N, Roberts A, Sadler K, Stavros T, Tamura R, Wood K, Xu P, Young K, Alies P, Badias F, Baker A, Bassi M, Beam C, Boulware D, Bounmananh L, Bream S, Deemer M, Freeman D, Gough J, Ginem J, Granger M, Holloway M, Kieffer M, Lane P, Law P, Linton C, Nallamshetty L, Oduah V, Parrimon Y, Paulus K, Pilger J, Ramiro J, Luvon AQ, Ritzie A, Sharma A, Shor X, Song A, Terry J, Weinberger M, Wootten J, Fradkin E, Leschek L, Spain C, Cowie S, Malozowski P, Savage G, Beck E, Blumberg R, Gubitosi-Klug L, Laffel R, Veatch D, Wallace J, Braun D, Brillon A, Lernmark B, Lo H, Mitchell A, Naji J, Nerup T, Orchard M, Steffes A, Tsiatis B, Zinman B, Loechelt L, Baden M, Green A, Weinberg S, Marcovina JP, Palmer A, Weinberg L, Yu W, Winter GS, Eisenbarth A, Shultz E, Batts K, Fitzpatrick M, Ramey R, Guerra C, Webb M, Romasco C, Greenbaum S, Lord D, VanBuecken W, Hao M, McCulloch D, Hefty K, Varner R, Goland E, Greenberg S, Pollack B, Nelson L, Looper L, DiMeglio M, Spall C, Evans-Molina M, Mantravadi J, Sanchez M, Mullen V, Patrick S, Woerner DM, Wilson T, Aye T, Esrey K, Barahona B, Baker H, Bitar C, Ghodrat M, Hamilton SE, Gitelman CT, Ferrara S, Sanda R, Wesch C, Torok P, Gottlieb J, Lykens C, Brill A, Michels A, Schauwecker MJ, Haller DA, Schatz MA, Atkinson LM, Jacobsen M, Cintron TM, Brusko CH, Wasserfall CE, Mathews JS, Skyler JM, Marks D, Baidal C, Blaschke D, Matheson A, Moran B, Nathan A, Street J, Leschyshyn B, Pappenfus B, Nelson N, Flaherty D, Becker K, Delallo D, Groscost K, Riley H, Rodriguez D, Henson E, Eyth W, Russell A, Brown F, Brendall K, Herold, Feldman L, Type 1 Diabetes TrialNet ATG-GCSF Study Group. Low-Dose Anti-Thymocyte Globulin (ATG) Preserves β-Cell Function and Improves HbA 1c in New-Onset Type 1 Diabetes. Diabetes Care 2018; 41:1917-1925. [PMID: 30012675 PMCID: PMC6105329 DOI: 10.2337/dc18-0494] [Show More Authors] [Citation(s) in RCA: 118] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 06/12/2018] [Indexed: 02/03/2023]
Abstract
OBJECTIVE A pilot study suggested that combination therapy with low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte colony-stimulating factor (GCSF) preserves C-peptide in established type 1 diabetes (T1D) (duration 4 months to 2 years). We hypothesized that 1) low-dose ATG/GCSF or 2) low-dose ATG alone would slow the decline of β-cell function in patients with new-onset T1D (duration <100 days). RESEARCH DESIGN AND METHODS A three-arm, randomized, double-masked, placebo-controlled trial was performed by the Type 1 Diabetes TrialNet Study Group in 89 subjects: 29 subjects randomized to ATG (2.5 mg/kg intravenously) followed by pegylated GCSF (6 mg subcutaneously every 2 weeks for 6 doses), 29 to ATG alone (2.5 mg/kg), and 31 to placebo. The primary end point was mean area under the curve (AUC) C-peptide during a 2-h mixed-meal tolerance test 1 year after initiation of therapy. Significance was defined as one-sided P value < 0.025. RESULTS The 1-year mean AUC C-peptide was significantly higher in subjects treated with ATG (0.646 nmol/L) versus placebo (0.406 nmol/L) (P = 0.0003) but not in those treated with ATG/GCSF (0.528 nmol/L) versus placebo (P = 0.031). HbA1c was significantly reduced at 1 year in subjects treated with ATG and ATG/GCSF, P = 0.002 and 0.011, respectively. CONCLUSIONS Low-dose ATG slowed decline of C-peptide and reduced HbA1c in new-onset T1D. Addition of GCSF did not enhance C-peptide preservation afforded by low-dose ATG. Future studies should be considered to determine whether low-dose ATG alone or in combination with other agents may prevent or delay the onset of the disease.
Collapse
Affiliation(s)
| | | | - Jay S. Skyler
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
| | | | | | | | | | | | - David Baidal
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
| | | | | | | | - Peter A. Gottlieb
- University of Colorado Barbara Davis Center for Childhood Diabetes, Aurora, CO
| | | | - Jennifer B. Marks
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
28
|
Abstract
PURPOSE OF REVIEW This review seeks to characterize emerging concepts related to disease-modifying therapy in type 1 diabetes. RECENT FINDINGS We begin by describing the new understanding that islet autoimmunity, as identified by the presence of islet autoantibodies, inevitably leads to clinical type 1 diabetes. This understanding informs the new staging paradigm for type 1 diabetes, which suggests that type 1 diabetes may be recognized and diagnosed long before symptoms develop. Although it is known that nearly all individuals with established islet autoimmunity will eventually develop symptomatic type 1 diabetes (T1D), individual characteristics such as age and biomarker profile may predict rate of disease progression and response to treatment and may therefore be used to individualize therapy. Key research supports the use of immunotherapy in TID, although a paradigm shift is necessary before immunotherapy may transition from clinical trials to clinical practice. Recent and ongoing research as it relates to these concepts is described throughout.
Collapse
Affiliation(s)
| | - Sandra Lord
- Benaroya Research Institute, Seattle, WA, USA
| | | |
Collapse
|
|
29
|
Abstract
Type 1 diabetes mellitus is a chronic state of insulin deficiency which results from destruction of beta cells by the immune system. The long term microvascular and macrovascular complications can be devastating. Since the discovery of insulin almost 100 years ago new medical therapies have improved the long-term survival for people with type 1 diabetes. Each year we come closer to discovering a cure but much work still needs to be done to eliminate this disease.
Collapse
Affiliation(s)
- Melanie Copenhaver
- Division of Pediatric Endocrinology, Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH, USA
| | - Robert P Hoffman
- Division of Pediatric Endocrinology, Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH, USA
| |
Collapse
|
|
30
|
Intestinal type 1 regulatory T cells migrate to periphery to suppress diabetogenic T cells and prevent diabetes development. Proc Natl Acad Sci U S A 2017; 114:10443-10448. [PMID: 28894001 DOI: 10.1073/pnas.1705599114] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Growing insight into the pathogenesis of autoimmune diseases and numerous studies in preclinical models highlights the potential of regulatory T cells to restore tolerance. By using non-obese diabetic (NOD) BDC2.5 TCR-transgenic (Tg), and IL-10 and Foxp3 double-reporter mice, we demonstrate that alteration of gut microbiota during cohousing experiments or treatment with anti-CD3 mAb significantly increase intestinal IL-10-producing type 1 regulatory T (Tr1) cells and decrease diabetes incidence. These intestinal antigen-specific Tr1 cells have the ability to migrate to the periphery via a variety of chemokine receptors such as CCR4, CCR5, and CCR7 and to suppress proliferation of Th1 cells in the pancreas. The ability of Tr1 cells to cure diabetes in NOD mice required IL-10 signaling, as Tr1 cells could not suppress CD4+ T cells with a dominant-negative IL-10R. Taken together, our data show a key role of intestinal Tr1 cells in the control of effector T cells and development of diabetes. Therefore, modulating gut-associated lymphoid tissue to boost Tr1 cells may be important in type 1 diabetes management.
Collapse
|
|
31
|
Guglielmi C, Williams SR, Del Toro R, Pozzilli P. Efficacy and safety of otelixizumab use in new-onset type 1 diabetes mellitus. Expert Opin Biol Ther 2017; 16:841-6. [PMID: 27145230 DOI: 10.1080/14712598.2016.1180363] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
INTRODUCTION Type 1 diabetes (T1DM) is an immune-mediated disease induced by antigen-specific T cells infiltrating pancreatic beta cells leading to the progressive loss of endogenous insulin secretion. AREAS COVERED The identification of specific components of the autoimmune response favoured the implementation of several immunomodulatory therapies including antiCD3 monoclonal antibody (mAb) called otelixizumab. Otelixizumab is a chimeric monoclonal antibody that targets the ε-chain of the CD3T-lymphocyte surface receptor that has been developed with the aim of short therapeutic courses capable of inducing a remission of T1DM. Clinical trials have been carried out with otelixizumab to evaluate its safety and efficacy, but despite positive results of Phase I and II studies, the results of Phase III studies have been contradictory. EXPERT OPINION High doses of otelixizumab have shown beneficial effects on beta cell function whereas a lower dose, which was tested to avoid the adverse effects associated with higher doses, was not effective on beta cells preservation. We believe that otelixizumab is a drug of potential interest for treating new onset T1DM patients and its use in combination with other immunomodulatory agents should be considered as a solution to circumvent adverse effects while maintaining efficacy.
Collapse
Affiliation(s)
- Chiara Guglielmi
- a Unit of Endocrinology and Diabetes, Department of Medicine , University Campus Bio-Medico di Roma , Rome , Italy
| | - Stefan Rhys Williams
- b Centre of Immunology, Barts and The London School of Medicine and Dentistry , Queen Mary, University of London , London , UK
| | - Rossella Del Toro
- a Unit of Endocrinology and Diabetes, Department of Medicine , University Campus Bio-Medico di Roma , Rome , Italy
| | - Paolo Pozzilli
- a Unit of Endocrinology and Diabetes, Department of Medicine , University Campus Bio-Medico di Roma , Rome , Italy.,b Centre of Immunology, Barts and The London School of Medicine and Dentistry , Queen Mary, University of London , London , UK
| |
Collapse
|
|
32
|
Affiliation(s)
- Johnny Ludvigsson
- Divsion of Pediatrics, Department of Clinical and Experimental Medicine, Linköping University, Linköping,Sweden
| |
Collapse
|
|
33
|
Abstract
In spite of modern techniques, the burden for patients with type 1 diabetes mellitus will not disappear, and type 1 diabetes will remain a life-threatening disease causing severe complications and increased mortality. We have to learn of ways to stop the destructive process, preserve residual insulin secretion or even improve the disease via β-cell regeneration. This will give a milder disease, a more stable metabolism, simpler treatment and perhaps even cure. Therapies based on single drugs have not shown sufficient efficacy; however, there are several treatments with encouraging efficacy and no apparent, or rather mild, adverse events. As the disease process is heterogeneous, treatments have to be chosen to fit relevant subgroups of patients, and step by step efficacy can possibly be improved by the use of combination therapies. Thus immunosuppressive therapies like anti-CD3 and anti-CD20 monoclonal antibodies might be combined with fusion proteins such as etanercept [tumor necrosis factor (TNF)-α inhibitor] and/or abatacept (CTLA4-Ig) early after onset to stop the destructive process, supported by β-cell protective agents. The effect may be prolonged by using autoantigen therapy [glutamate decarboxylase (GAD) proinsulin], and by adding agents facilitating β-cell regeneration [e.g. glucagon-like peptide-1 (GLP-1)] there should be a good chance to make the disease milder, perhaps leading to cure in some patients.
Collapse
Affiliation(s)
- Johnny Ludvigsson
- Division of Pediatrics, Department of Clinical and Experimental Medicine, Linköping University, 58185, Linköping, Sweden.
| |
Collapse
|
|
34
|
Pilla SJ, Quan AQ, Germain-Lee EL, Hellmann DB, Mathioudakis NN. Immune-Modulating Therapy for Rheumatologic Disease: Implications for Patients with Diabetes. Curr Diab Rep 2016; 16:91. [PMID: 27525682 PMCID: PMC6031126 DOI: 10.1007/s11892-016-0792-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Immune modulators used to treat rheumatologic disease have diverse endocrine effects in patients with diabetes. Providers should be aware of these effects given that diabetes and rheumatologic disease overlap in prevalence and cardiovascular morbidity. In patients with type 1 diabetes, clinical trials have demonstrated that immune modulators used early in the disease can improve pancreatic function, though their efficacy in adults with longstanding autoimmune diabetes is unknown. In patients with type 2 diabetes, hydroxychloroquine is an effective antihyperglycemic and may be preferred for rheumatologic use in patients with difficult glycemic control. In patients without diabetes, hydroxychloroquine and tumor necrosis factor (TNF) inhibitors have been found to decrease diabetes incidence in observational studies. Additionally, dapsone and sulfasalazine alter erythrocyte survival resulting in inaccurate HbA1c values. These multifaceted effects of immune modulators create a need for coordinated care between providers treating patients with diabetes to individualize medication selection and prevent hypoglycemic events. More research is needed to determine the long-term outcomes of immune modulators in patients with diabetes.
Collapse
Affiliation(s)
- Scott J Pilla
- General Internal Medicine, Johns Hopkins University, 2024 E. Monument St, Room 2-604A, Baltimore, MD, 21205, USA
| | - Amy Q Quan
- Johns Hopkins School of Medicine, 2202 E Fairmount Ave, Baltimore, MD, 21231, USA
| | - Emily L Germain-Lee
- Department of Pediatrics, Division of Pediatric Endocrinology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
- Kennedy Krieger Institute, Broadway, Room 583, Baltimore, MD, 801 N, USA
| | - David B Hellmann
- Department of Medicine, Johns Hopkins University School of Medicine and Johns Hopkins, Bayview, Johns Hopkins Bayview Medical Center, Mason F. Lord Building, Center Tower, Room 322, 5200 Eastern Avenue, Baltimore, MD, 21224, USA
| | - Nestoras N Mathioudakis
- Endocrinology, Diabetes, and Metabolism, Johns Hopkins University, 1830 E. Monument Street, Suite 333, Baltimore, MD, 21287, USA.
| |
Collapse
|
|
35
|
Vanikar AV, Trivedi HL, Thakkar UG. Stem cell therapy emerging as the key player in treating type 1 diabetes mellitus. Cytotherapy 2016; 18:1077-86. [PMID: 27424148 DOI: 10.1016/j.jcyt.2016.06.006] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Revised: 05/24/2016] [Accepted: 06/07/2016] [Indexed: 02/06/2023]
Abstract
Type 1 diabetes mellitus (T1DM) is an autoimmune disease causing progressive destruction of pancreatic β cells, ultimately resulting in loss of insulin secretion producing hyperglycemia usually affecting children. Replacement of damaged β cells by cell therapy can treat it. Currently available strategies are insulin replacement and islet/pancreas transplantation. Unfortunately these offer rescue for variable duration due to development of autoantibodies. For pancreas/islet transplantation a deceased donor is required and various shortfalls of treatment include quantum, cumbersome technique, immune rejection and limited availability of donors. Stem cell therapy with assistance of cellular reprogramming and β-cell regeneration can open up new therapeutic modalities. The present review describes the history and current knowledge of T1DM, evolution of cell therapies and different cellular therapies to cure this condition.
Collapse
Affiliation(s)
- Aruna V Vanikar
- Department of Regenerative Medicine and Stem Cell Therapy, G.R. Doshi and K.M. Mehta Institute of Kidney Diseases & Research Centre, Dr. H.L. Trivedi Institute of Transplantation Sciences, Gujarat, India; Department of Pathology, Laboratory Medicine, Transfusion Services and Immunohematology, G.R. Doshi and K.M. Mehta Institute of Kidney Diseases & Research Centre, Dr. H.L. Trivedi Institute of Transplantation Sciences, Gujarat, India.
| | - Hargovind L Trivedi
- Department of Regenerative Medicine and Stem Cell Therapy, G.R. Doshi and K.M. Mehta Institute of Kidney Diseases & Research Centre, Dr. H.L. Trivedi Institute of Transplantation Sciences, Gujarat, India; Department of Nephrology and Transplantation Medicine, G.R. Doshi and K.M. Mehta Institute of Kidney Diseases & Research Centre, Dr. H.L. Trivedi Institute of Transplantation Sciences, Gujarat, India
| | - Umang G Thakkar
- Department of Regenerative Medicine and Stem Cell Therapy, G.R. Doshi and K.M. Mehta Institute of Kidney Diseases & Research Centre, Dr. H.L. Trivedi Institute of Transplantation Sciences, Gujarat, India
| |
Collapse
|
|
36
|
Garyu JW, Meffre E, Cotsapas C, Herold KC. Progress and challenges for treating Type 1 diabetes. J Autoimmun 2016; 71:1-9. [PMID: 27210268 PMCID: PMC4903889 DOI: 10.1016/j.jaut.2016.04.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Accepted: 04/24/2016] [Indexed: 02/09/2023]
Abstract
It has been more than 30 years since the initial trials of Cyclosporin A to treat patients with new onset Type 1 diabetes (T1D). Since that time, there have been insights into genetic predisposition to the disease, the failures of immune tolerance, and mechanisms that cause the immune mediated β cell destruction. The genetic loci associated affect lymphocyte development and tolerance mechanisms. Discoveries related to the roles of specific immune responses gene such as the major histocompatibility complex, PTPN22, CTLA-4, IL-2RA, as well as the mechanisms of antigen presentation in the thymus have suggested ways in which autoreactivity may follow changes in the functions of these genes that are associated with risk. Antigens that are recognized by the immune system in patients with T1D have been identified. With this information, insights into the novel cellular mechanisms leading to the initiation and orchestration of β cell killing have been developed such as the presentation of unique antigens within the islets. Clinical trials have been performed, some of which have shown efficacy in improving β cell function but none have been able to permanently prevent loss of insulin secretion. The reasons for the lack of long term success are not clear but may include the heterogeneity of the immune response and in individual responses to immune therapies, recurrence of autoimmunity after the initial effects of the therapies, or even intrinsic mechanisms of β cell death that proceeds independently of immune attack after initiation of the disease. In this review, we cover developments that have led to new therapeutics and characteristics of patients who may show the most benefits from therapies. We also identify areas of incomplete understanding that might be addressed to develop more effective therapeutic strategies.
Collapse
Affiliation(s)
- Justin W Garyu
- Department of Immunobiology, Yale University, New Haven, CT, USA
| | - Eric Meffre
- Department of Immunobiology, Yale University, New Haven, CT, USA
| | - Chris Cotsapas
- Department of Neurology, Yale University, New Haven, CT, USA
| | - Kevan C Herold
- Department of Immunobiology, Yale University, New Haven, CT, USA; Department of Internal Medicine, Yale University, New Haven, CT, USA
| |
Collapse
|
|
37
|
Li X, Cheng J, Zhou Z. Revisiting multiple models of progression of β-cell loss of function in type 1 diabetes: Significance for prevention and cure. J Diabetes 2016; 8:460-9. [PMID: 26754489 DOI: 10.1111/1753-0407.12376] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2015] [Revised: 12/24/2015] [Accepted: 01/07/2016] [Indexed: 01/12/2023] Open
Abstract
Type 1 diabetes (T1D) results from a chronic autoimmune process that leads to β-cell destruction and exogenous insulin dependence. The natural history of T1D proposed by Eisenbarth suggested six relatively independent stages over the course of the entire disease process, which was considered to be linear and chronic. Based on this classical theory, immunotherapies aim to prevent or reverse all these periods of β-cell loss. Over the past 30 years, much novel information about the pathogenesis of T1D proved that there are complex metabolic changes occurring throughout the entire disease process. Therefore, new possible models for the natural history of the disease have been proposed; these models, in turn, may help facilitate fresh avenues for the prevention and cure of T1D. Herein, we briefly review recent findings in this field of research, with the aim of providing a better theoretical basis for clinical practice.
Collapse
Affiliation(s)
- Xia Li
- Institute of Metabolism and Endocrinology, The Second Xiangya Hospital and the Diabetes Center, Key Laboratory of Diabetes Immunology, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Central South University, Changsha, Hunan, China
| | - Jin Cheng
- Institute of Metabolism and Endocrinology, The Second Xiangya Hospital and the Diabetes Center, Key Laboratory of Diabetes Immunology, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Central South University, Changsha, Hunan, China
| | - Zhiguang Zhou
- Institute of Metabolism and Endocrinology, The Second Xiangya Hospital and the Diabetes Center, Key Laboratory of Diabetes Immunology, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Central South University, Changsha, Hunan, China
| |
Collapse
|
|
38
|
Szendroedi J, Saxena A, Weber KS, Strassburger K, Herder C, Burkart V, Nowotny B, Icks A, Kuss O, Ziegler D, Al-Hasani H, Müssig K, Roden M. Cohort profile: the German Diabetes Study (GDS). Cardiovasc Diabetol 2016; 15:59. [PMID: 27053136 PMCID: PMC4823856 DOI: 10.1186/s12933-016-0374-9] [Citation(s) in RCA: 105] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 03/24/2016] [Indexed: 12/16/2022] Open
Abstract
Background The German Diabetes Study (GDS) is a prospective longitudinal cohort study describing the impact of subphenotypes on the course of the disease. GDS aims at identifying prognostic factors and mechanisms underlying the development of related comorbidities. Study design and methods The study comprises intensive phenotyping within 12 months after clinical diagnosis, at 5-year intervals for 20 years and annual telephone interviews in between. Dynamic tests, including glucagon, mixed meal, intravenous glucose tolerance and hyperinsulinemic clamp tests, serve to assess beta-cell function and tissue-specific insulin sensitivity. Magnetic resonance imaging and multinuclei spectroscopy allow quantifying whole-body fat distribution, tissue-specific lipid deposition and energy metabolism. Comprehensive analyses of microvascular (nerve, eye, kidney) and macrovascular (endothelial, cardiorespiratory) morphology and function enable identification and monitoring of comorbidities. The GDS biobank stores specimens from blood, stool, skeletal muscle, subcutaneous adipose tissue and skin for future analyses including multiomics, expression profiles and histology. Repeated questionnaires on socioeconomic conditions, patient-reported outcomes as quality of life, health-related behavior as physical activity and nutritional habits are a specific asset of GDS. This study will recruit 3000 patients and a group of humans without familiy history of diabetes. 237 type 1 and 456 type 2 diabetes patients have been already included. Electronic supplementary material The online version of this article (doi:10.1186/s12933-016-0374-9) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Julia Szendroedi
- Institute for Clinical Diabetology, Leibniz Institute for Diabetes Research, German Diabetes Center at Heinrich Heine University, Düsseldorf, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany.,Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Aaruni Saxena
- Institute for Clinical Diabetology, Leibniz Institute for Diabetes Research, German Diabetes Center at Heinrich Heine University, Düsseldorf, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany.,Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Katharina S Weber
- Institute for Clinical Diabetology, Leibniz Institute for Diabetes Research, German Diabetes Center at Heinrich Heine University, Düsseldorf, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Klaus Strassburger
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany.,Institute for Biometrics and Epidemiology, Leibniz Institute for Diabetes Research, German Diabetes Center at Heinrich Heine University, Düsseldorf, Germany
| | - Christian Herder
- Institute for Clinical Diabetology, Leibniz Institute for Diabetes Research, German Diabetes Center at Heinrich Heine University, Düsseldorf, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Volker Burkart
- Institute for Clinical Diabetology, Leibniz Institute for Diabetes Research, German Diabetes Center at Heinrich Heine University, Düsseldorf, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Bettina Nowotny
- Institute for Clinical Diabetology, Leibniz Institute for Diabetes Research, German Diabetes Center at Heinrich Heine University, Düsseldorf, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Andrea Icks
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany.,Institute for Biometrics and Epidemiology, Leibniz Institute for Diabetes Research, German Diabetes Center at Heinrich Heine University, Düsseldorf, Germany.,Public Health Unit, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Oliver Kuss
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany.,Institute for Biometrics and Epidemiology, Leibniz Institute for Diabetes Research, German Diabetes Center at Heinrich Heine University, Düsseldorf, Germany
| | - Dan Ziegler
- Institute for Clinical Diabetology, Leibniz Institute for Diabetes Research, German Diabetes Center at Heinrich Heine University, Düsseldorf, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany.,Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Hadi Al-Hasani
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany.,Institute for Clinical Biochemistry and Pathobiochemistry German Diabetes Center, Leibniz Institute for Diabetes Research, Düsseldorf, Germany
| | - Karsten Müssig
- Institute for Clinical Diabetology, Leibniz Institute for Diabetes Research, German Diabetes Center at Heinrich Heine University, Düsseldorf, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany.,Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Michael Roden
- Institute for Clinical Diabetology, Leibniz Institute for Diabetes Research, German Diabetes Center at Heinrich Heine University, Düsseldorf, Germany. .,German Center for Diabetes Research (DZD), München-Neuherberg, Germany. .,Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
| | | |
Collapse
|
|
39
|
Blasetti A, Di Giulio C, Tumini S, Provenzano M, Rapino D, Comegna L, Prezioso G, Chiuri R, Franchini S, Chiarelli F, Stuppia L. Role of the C1858T polymorphism of protein tyrosine phosphatase non-receptor type 22 (PTPN22) in children and adolescents with type 1 diabetes. THE PHARMACOGENOMICS JOURNAL 2016; 17:186-191. [DOI: 10.1038/tpj.2016.6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/04/2015] [Revised: 11/24/2015] [Accepted: 01/20/2016] [Indexed: 01/18/2023]
|
|
40
|
Snarski E, Milczarczyk A, Hałaburda K, Torosian T, Paluszewska M, Urbanowska E, Król M, Boguradzki P, Jedynasty K, Franek E, Wiktor-Jedrzejczak W. Immunoablation and autologous hematopoietic stem cell transplantation in the treatment of new-onset type 1 diabetes mellitus: long-term observations. Bone Marrow Transplant 2015; 51:398-402. [PMID: 26642342 DOI: 10.1038/bmt.2015.294] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Revised: 09/29/2015] [Accepted: 10/18/2015] [Indexed: 12/30/2022]
Abstract
The activity of the autoimmune mechanism underlying type 1 diabetes mellitus (T1DM) can be suppressed when immunoablation and autologous hematopoietic stem cell transplantation (AHSCT) are applied early in the course of the disease. We report here a single centre experience with this treatment modality. Twenty-four patients underwent a AHSCT preceded by immunoablative conditioning with high-dose cyclophosphamide and anti-thymocyte globulin. During the 52-month median time of follow-up 20 out of 23 patients (87%) remained for at least 9.5 months without the use of exogenous insulin. The median time of T1DM remission for these patients was 31 months (range of 9.5-80 months). Among the patients available for follow-up (n=20), four remain insulin free (for 80, 61, 42 and 34 months). The average glycated hemoglobin (HbA1c) concentrations were 10.9% at diagnosis, 5.9% at 1 year, 6.4% at 2 years, 6.8% at 3 years and 7.1% at 4 years after AHSCT. No severe complications of diabetes were seen, however one of the patients died of pseudomonas sepsis in the course of neutropenia after AHSCT. AHSCT leads to a remission of T1DM with good glycemic control in the vast majority of patients, with the period of remission lasting over 5 years in some patients.
Collapse
Affiliation(s)
- E Snarski
- Department of Hematology, Oncology and Internal Medicine, Medical University of Warsaw, Warszawa, Poland
| | - A Milczarczyk
- Department of Internal Medicine, Diabetology and Endocrinology, Central Hospital, Ministry of Internal Affairs and Administration, Warszawa, Poland
| | - K Hałaburda
- Department of Hematology, Oncology and Internal Medicine, Medical University of Warsaw, Warszawa, Poland
| | - T Torosian
- Department of Hematology, Oncology and Internal Medicine, Medical University of Warsaw, Warszawa, Poland
| | - M Paluszewska
- Department of Hematology, Oncology and Internal Medicine, Medical University of Warsaw, Warszawa, Poland
| | - E Urbanowska
- Department of Hematology, Oncology and Internal Medicine, Medical University of Warsaw, Warszawa, Poland
| | - M Król
- Department of Hematology, Oncology and Internal Medicine, Medical University of Warsaw, Warszawa, Poland
| | - P Boguradzki
- Department of Hematology, Oncology and Internal Medicine, Medical University of Warsaw, Warszawa, Poland
| | - K Jedynasty
- Department of Internal Medicine, Diabetology and Endocrinology, Central Hospital, Ministry of Internal Affairs and Administration, Warszawa, Poland
| | - E Franek
- Department of Internal Medicine, Diabetology and Endocrinology, Central Hospital, Ministry of Internal Affairs and Administration, Warszawa, Poland.,Mossakowski Medical Research Centre, Polish Academy of Sciences, Warszawa, Poland
| | - W Wiktor-Jedrzejczak
- Department of Hematology, Oncology and Internal Medicine, Medical University of Warsaw, Warszawa, Poland
| |
Collapse
|
|
41
|
Mannering SI, Pathiraja V, Kay TWH. The case for an autoimmune aetiology of type 1 diabetes. Clin Exp Immunol 2015; 183:8-15. [PMID: 26313217 DOI: 10.1111/cei.12699] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/25/2015] [Indexed: 01/10/2023] Open
Abstract
Type 1 diabetes (T1D) develops when there are insufficient insulin-producing beta cells to maintain glucose homeostasis. The prevailing view has been that T1D is caused by immune-mediated destruction of the pancreatic beta cells. However, several recent papers have challenged the long-standing paradigm describing T1D as a tissue-specific autoimmune disease. These authors have highlighted the gaps in our knowledge and understanding of the aetiology of T1D in humans. Here we review the evidence and argue the case for the autoimmune basis of human T1D. In particular, recent analysis of human islet-infiltrating T cells brings important new evidence to this question. Further data in support of the autoimmune basis of T1D from many fields, including genetics, experimental therapies and immunology, is discussed. Finally, we highlight some of the persistent questions relating to the pathogenesis of human type 1 diabetes that remain to be answered.
Collapse
Affiliation(s)
- S I Mannering
- Immunology and Diabetes Unit, St Vincent's Institute of Medical Research.,Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, VIC, Australia
| | - V Pathiraja
- Immunology and Diabetes Unit, St Vincent's Institute of Medical Research.,Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, VIC, Australia
| | - T W H Kay
- Immunology and Diabetes Unit, St Vincent's Institute of Medical Research.,Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, VIC, Australia
| |
Collapse
|
|
42
|
Wherrett DK. Trials in the prevention of type 1 diabetes: current and future. Can J Diabetes 2015; 38:279-84. [PMID: 25092646 DOI: 10.1016/j.jcjd.2014.05.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2014] [Revised: 05/04/2014] [Accepted: 05/05/2014] [Indexed: 12/19/2022]
Abstract
A major thrust in type 1 diabetes research is stopping the destruction of beta cells that leads to type 1 diabetes. Research over the past 30 years has defined genetic factors and evidence of autoimmunity that have led to the development of robust prediction models in those at high risk for type 1 diabetes. The ability to identify those at risk and the development of new agents and of collaborative research networks has led to multiple trials aimed at preventing beta cell loss. Trials at all stages of beta cell loss have been conducted: primary prevention (prior to the development of autoimmunity); secondary prevention (after autoantibodies are found) and tertiary prevention (intervening after diagnosis to maintain remaining beta cells). Studies have shown mixed results; evidence of maintained insulin secretion after the time of diagnosis has been described in a number of studies, and primary and secondary prevention is proving to be elusive. Much has been learned from the increasing number of studies in the field in terms of network creation, study design and choice of intervention that will facilitate new avenues of investigation.
Collapse
Affiliation(s)
- Diane K Wherrett
- Division of Endocrinology, Department of Pediatrics, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.
| |
Collapse
|
|
43
|
Vudattu NK, Herold KC. Treatment of new onset type 1 diabetes with teplizumab: successes and pitfalls in development. Expert Opin Biol Ther 2015; 14:377-85. [PMID: 24517093 DOI: 10.1517/14712598.2014.881797] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
INTRODUCTION Type 1 diabetes is an organ-specific autoimmune disease, characterized by selective destruction of insulin-producing pancreatic β-cells by T-cell-mediated inflammation. Beginning with studies of cyclosporin A in the 1980s, but with more activity in the past decade, there have been a number of clinical trials to test whether immunotherapies can arrest the decline in C-peptide, which is associated with progression of type 1 diabetes leading to the metabolic instability that characterizes the disease. One of the most promising agents, teplizumab , is an FcR-nonbinding anti-CD3 monoclonal antibody that has been tested in Phase II - III clinical trials and was shown to preserve the C-peptide levels and reduce the need for exogenous insulin. AREAS COVERED In this review, we discuss the recent update on clinical data obtained from trials of teplizumab in type 1 diabetes, the drug's postulated mechanism of action and the identification of responders to therapy. We highlight the results of recent trials as well as the lessons that have been learned from the clinical trials involving selection of end points and the inclusion of diverse study populations. EXPERT OPINION Teplizumab has been shown to preserve β cell function in patients; however, it does not represent a 'cure' for patients, and its efficacy does entail a significant advance in arresting the progression of the disease toward complete insulin deficiency and reliance on exogenous insulin.
Collapse
Affiliation(s)
- Nalini K Vudattu
- Yale University, Department of Immunobiology and Internal Medicine , 300 George St, #353E, New Haven, CT 06520 , USA +1 203 785 6507 ;
| | | |
Collapse
|
|
44
|
Skyler JS. Prevention and reversal of type 1 diabetes--past challenges and future opportunities. Diabetes Care 2015; 38:997-1007. [PMID: 25998292 DOI: 10.2337/dc15-0349] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Over the past three decades there have been a number of clinical trials directed at interdicting the type 1 diabetes (T1D) disease process in an attempt to prevent the development of the disease in those at increased risk or to stabilize-potentially even reverse-the disease in people with T1D, usually of recent onset. Unfortunately, to date there has been no prevention trial that has resulted in delay or prevention of T1D. And, trials in people with T1D have had mixed results with some showing promise with at least transient improvement in β-cell function compared with randomized control groups, while others have failed to slow the decline in β-cell function when compared with placebo. This Perspective will assess the past and present challenges in this effort and provide an outline for potential future opportunities.
Collapse
Affiliation(s)
- Jay S Skyler
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
| |
Collapse
|
|
45
|
Abstract
Studies over the past 35 years in the nonobese diabetic (NOD) mouse have shown that a number of agents can prevent or even reverse type 1 diabetes mellitus (T1DM); however, these successes have not been replicated in human clinical trials. Although some of these interventions have delayed disease onset or progression in subsets of participants, none have resulted in a complete cure. Even in the most robust responders, the treatments do not permanently preserve insulin secretion or stimulate the proliferation of β cells, as has been observed in mice. The shortfalls of translating NOD mouse studies into the clinic questions the value of using this model in preclinical studies. In this Perspectives, we suggest how immunological and genetic differences between NOD mice and humans might contribute to the differential outcomes and suggest ways in which the mouse model might be modified or applied as a tool to develop treatments and improve understanding of clinical trial outcomes.
Collapse
Affiliation(s)
- James C Reed
- Department of Immunobiology, 300 George Street, #353E, New Haven, CT 06520, USA
| | - Kevan C Herold
- Department of Immunobiology, Department of Internal Medicine, Yale University, 300 George Street, #353E, New Haven, CT 06520, USA
| |
Collapse
|
|
46
|
Askenasy N. Less Is More: The Detrimental Consequences of Immunosuppressive Therapy in the Treatment of Type-1 Diabetes. Int Rev Immunol 2015; 34:523-37. [DOI: 10.3109/08830185.2015.1010723] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
|
|
47
|
Haller MJ, Gitelman SE, Gottlieb PA, Michels AW, Rosenthal SM, Shuster JJ, Zou B, Brusko TM, Hulme MA, Wasserfall CH, Mathews CE, Atkinson MA, Schatz DA. Anti-thymocyte globulin/G-CSF treatment preserves β cell function in patients with established type 1 diabetes. J Clin Invest 2014; 125:448-55. [PMID: 25500887 DOI: 10.1172/jci78492] [Citation(s) in RCA: 125] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Accepted: 10/31/2014] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Previous efforts to preserve β cell function in individuals with type 1 diabetes (T1D) have focused largely on the use of single immunomodulatory agents administered within 100 days of diagnosis. Based on human and preclinical studies, we hypothesized that a combination of low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte CSF (G-CSF) would preserve β cell function in patients with established T1D (duration of T1D >4 months and <2 years). METHODS A randomized, single-blinded, placebo-controlled trial was performed on 25 subjects: 17 subjects received ATG (2.5 mg/kg intravenously) followed by pegylated G-CSF (6 mg subcutaneously every 2 weeks for 6 doses) and 8 subjects received placebo. The primary outcome was the 1-year change in AUC C-peptide following a 2-hour mixed-meal tolerance test (MMTT). At baseline, the age (mean ± SD) was 24.6 ± 10 years; mean BMI was 25.4 ± 5.2 kg/m²; mean A1c was 6.5% ± 1.1%; insulin use was 0.31 ± 0.22 units/kg/d; and length of diagnosis was 1 ± 0.5 years. RESULTS Combination ATG/G-CSF treatment tended to preserve β cell function in patients with established T1D. The mean difference in MMTT-stimulated AUC C-peptide between treated and placebo subjects was 0.28 nmol/l/min (95% CI 0.001-0.552, P = 0.050). A1c was lower in ATG/G-CSF-treated subjects at the 6-month study visit. ATG/G-CSF therapy was associated with relative preservation of Tregs. CONCLUSIONS Patients with established T1D may benefit from combination immunotherapy approaches to preserve β cell function. Further studies are needed to determine whether such approaches may prevent or delay the onset of the disease. TRIAL REGISTRATION Clinicaltrials.gov NCT01106157. FUNDING The Leona M. and Harry B. Helmsley Charitable Trust and Sanofi.
Collapse
|
|
48
|
Abstract
PURPOSE OF REVIEW Although insulin is lifesaving and sustaining for those with type 1 diabetes (T1D), curing the disease will be much more complex than simple replacement of this hormone. T1D is an autoimmune disease orchestrated by T cells, and includes many arms of the immune response. Tremendous effort has gone into understanding its underlying immune, genetic, and environmental causes, and this progress has led to immunologically based clinical trials in T1D. This review will focus primarily on the clinical trials of the past decade that have attempted to translate these fundamental findings. RECENT FINDINGS It is known that powerful, nonspecific immune suppressants can temporarily slow the course of newly diagnosed T1D, yet are too toxic for long-term use, especially in children. Recent clinical trials to reverse T1D have used newly developed therapies that target specific components of the immune process believed to be involved with T1D. Although well justified and designed, no recent approach has resulted in clinical remission and few have had any effect on disease course. SUMMARY Advances in our fundamental understanding of how the human diabetes immune response is activated and regulated coupled with lessons that have been learnt from the most recent era of completed trials are guiding us toward the development of more effective, multipronged therapies to ablate diabetes autoimmunity, restore immune tolerance, preserve β cells, and, ultimately, improve the lives of patients with T1D.
Collapse
Affiliation(s)
- Mark R Rigby
- aIndiana University School of Medicine and Riley Hospital for Children at IU Health, Indianapolis, Indiana bImmune Tolerance Network, San Francisco, California, USA
| | | |
Collapse
|
|
49
|
Bruni A, Gala-Lopez B, Pepper AR, Abualhassan NS, Shapiro AMJ. Islet cell transplantation for the treatment of type 1 diabetes: recent advances and future challenges. Diabetes Metab Syndr Obes 2014; 7:211-23. [PMID: 25018643 PMCID: PMC4075233 DOI: 10.2147/dmso.s50789] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Islet transplantation is a well-established therapeutic treatment for a subset of patients with complicated type I diabetes mellitus. Prior to the Edmonton Protocol, only 9% of the 267 islet transplant recipients since 1999 were insulin independent for >1 year. In 2000, the Edmonton group reported the achievement of insulin independence in seven consecutive patients, which in a collaborative team effort propagated expansion of clinical islet transplantation centers worldwide in an effort to ameliorate the consequences of this disease. To date, clinical islet transplantation has established improved success with insulin independence rates up to 5 years post-transplant with minimal complications. In spite of marked clinical success, donor availability and selection, engraftment, and side effects of immunosuppression remain as existing obstacles to be addressed to further improve this therapy. Clinical trials to improve engraftment, the availability of insulin-producing cell sources, as well as alternative transplant sites are currently under investigation to expand treatment. With ongoing experimental and clinical studies, islet transplantation continues to be an exciting and attractive therapy to treat type I diabetes mellitus with the prospect of shifting from a treatment for some to a cure for all.
Collapse
Affiliation(s)
- Anthony Bruni
- Clinical Islet Transplant Program and Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Boris Gala-Lopez
- Clinical Islet Transplant Program and Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Andrew R Pepper
- Clinical Islet Transplant Program and Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Nasser S Abualhassan
- Clinical Islet Transplant Program and Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - AM James Shapiro
- Clinical Islet Transplant Program and Department of Surgery, University of Alberta, Edmonton, AB, Canada
| |
Collapse
|
|
50
|
Abstract
Type 1 diabetes mellitus (T1DM) is the result of autoimmune destruction of pancreatic β cells in genetically predisposed individuals with impaired immune regulation. The insufficiency in the modulation of immune attacks on the β cells might be partly due to genetic causes; indeed, several of the genetic variants that predispose individuals to T1DM have functional features of impaired immune regulation. Whilst defects in immune regulation in patients with T1DM have been identified, many patients seem to have immune regulatory capacities that are indistinguishable from those of healthy individuals. Insight into the regulation of islet autoimmunity might enable us to restore immune imbalances with therapeutic interventions. In this Review, we discuss the current knowledge on immune regulation and dysfunction in humans that is the basis of tissue-specific immune regulation as an alternative to generalized immune suppression.
Collapse
Affiliation(s)
- Bart O Roep
- Leiden University Medical Center, Department of Immunohaematology & Blood Transfusion, P. O. Box 9600, NL-2300 RC Leiden, Netherlands
| | - Timothy I M Tree
- Department of Immunobiology, King's College London, School of Medicine, London SE1 9RT, UK
| |
Collapse
|