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Salame G, Hakim V, Dagher C, Daou RM, Dada AE, Nassif L, Ghadieh HE, Azar S, Bazzi S, Harb F. Immunotherapy as a treatment for type 1 diabetes mellitus in children and young adults: A comprehensive systematic review and meta-analysis. PLoS One 2025; 20:e0321727. [PMID: 40215252 PMCID: PMC11990578 DOI: 10.1371/journal.pone.0321727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 03/11/2025] [Indexed: 04/14/2025] Open
Abstract
BACKGROUND AND OBJECTIVE Type 1 diabetes mellitus (T1DM) is characterized by the loss of pancreatic cells, resulting in total insulin insufficiency. According to the Diabetes Control and Complications Trial, T1DM treatment aims to achieve appropriate glycemic control and to prevent and avoid repeated episodes of hypoglycemia. Insulin therapy alone addresses the symptoms of the disease but fails to target the underlying pathophysiology of T1DM in children despite continuous efforts to enhance insulin regimens. Therefore, immunotherapy-based approaches have been considered potential treatments for T1DM in children since they can regulate the autoimmune responses and enhance the children's quality of life by reducing their daily dose intake of insulin. METHODS In this meta-analysis, we have covered a few immunotherapeutic options based on preclinical and clinical data, namely, Teplizumab, Golimumab, Imatinib, Etanercept, Canakinumab, Ladarixin, Ala-Ala, Anakinra, and Otelixizumab in reliable databases such as Pubmed, Google Scholar, and Cochrane. SPSS was used for statistical analysis. Mean difference (MD) and standard mean difference (SMD) were used to evaluate the outcomes with a 95% confidence interval (CI). RESULTS To assess the effect of immunotherapy on the patients' daily dosage of insulin and their HbA1c and C-peptide levels, data from twelve trials were combined and synthesized. Because of the high levels of heterogeneity in the selected studies, a random-effects model was used for analysis. The combined data showed that patients receiving immunotherapy had higher C-peptide levels (Mean Difference (MD) = 1.51; 95% Confidence Interval (CI): [-2.56, 5.58]); however, this difference was not statistically significant (p = 0.42). On the other hand, patients in the immunotherapy group had significantly decreased HbA1c levels (MD = -0.63; 95% CI: [-1.18, -0.07]; p = 0.03), indicating that immunotherapy had a positive impact on glycemic management. Additionally, patients receiving immunotherapy exhibited a drop in their daily insulin dosage (MD = -1.15; 95% CI: [-2.59, 0.28]); however, this drop failed to achieve statistical significance (p = 0.10), thus indicating the need for additional research. CONCLUSION This meta-analysis aimed to assess the effectiveness of immunotherapy in treating T1DM by examining its effects on the patients' required dose of insulin, C-peptide, and HbA1c levels. While some studies failed to show desired results, the overall effect was an increase in C-peptide levels and a decrease in HbA1c levels. However, the study did not achieve statistical significance for insulin dosing. The main study's strength is its focus on randomized clinical trials which is considered among the highest levels of epidemiological evidence. Therefore, further research is required to minimize the gaps and to explore immunotherapy-based drugs as potential treatments for T1DM.
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Affiliation(s)
- Gaelle Salame
- Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
| | - Vincent Hakim
- Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
| | - Clara Dagher
- Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
| | - Rose-Mary Daou
- Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
| | - Anthony El Dada
- Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
| | - Lea Nassif
- Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
| | - Hilda E. Ghadieh
- Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
- AUB Diabetes, American University of Beirut, Beirut, Lebanon
| | - Sami Azar
- Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
- AUB Diabetes, American University of Beirut, Beirut, Lebanon
| | - Samer Bazzi
- Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
| | - Frederic Harb
- Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
- AUB Diabetes, American University of Beirut, Beirut, Lebanon
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2
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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.
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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
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Ajmal N, Bogart MC, Khan P, Max-Harry IM, Healy AM, Nunemaker CS. Identifying Promising Immunomodulators for Type 1 Diabetes (T1D) and Islet Transplantation. J Diabetes Res 2024; 2024:5151171. [PMID: 39735417 PMCID: PMC11679277 DOI: 10.1155/jdr/5151171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Accepted: 12/04/2024] [Indexed: 12/31/2024] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune chronic disorder that damages beta cells in the pancreatic islets of Langerhans and results in hyperglycemia due to the loss of insulin. Exogenous insulin therapy can save lives but does not stop disease progression. Thus, an effective therapy may require beta cell restoration and suppression of the autoimmune response. However, currently, there are no treatment options available that can reverse T1D. Within the National Clinical Trial (NCT) database, a majority of over 3000 trials to treat T1D are devoted to insulin therapy. This review focuses on noninsulin pharmacological therapies, specifically immunomodulators. Many investigational new drugs fall under this category, such as the recently FDA-approved CD3 monoclonal antibody teplizumab to delay the onset of T1D. In total, we identified 39 different immunomodulatory investigational drugs. FDA-approved teplizumab for Stage 2 T1D is discussed along with other immunomodulators that have been tested in Phase 3 clinical trials or higher, including otelixizumab (another anti-CD3 monoclonal antibody), daclizumab (an anti-CD25 monoclonal antibody), ladarixin (CXCR1/2 inhibitor), and antithymocyte globulin (ATG). Immunomodulators also play roles in islet transplantation and cellular therapies like FDA-approved Lantidra. Several immunomodulators involved in Phase 3 clinical studies of islet transplantation are also discussed, including alemtuzumab, basiliximab, etanercept, and reparixin, some already FDA-approved for other uses. These include alemtuzumab, basiliximab, etanercept, and reparixin, some of which have been FDA-approved for other uses. This review provides background, mechanism of action, results of completed trials, and adverse effects as well as details regarding ongoing clinical trials for each of these immunomodulators. Trial Registration: ClinicalTrials.gov identifier: NCT03875729, NCT01030861, NCT00129259, NCT00385697, NCT01280682; NCT03929601, NCT04598893, NCT05757713, NCT00678886, NCT01123083, NCT00064714, NCT00468117, NCT04628481, NCT01106157, NCT02215200, NCT00331162, NCT00679042, NCT01220856, NCT01817959.
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Affiliation(s)
- Nida Ajmal
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA
- Translational Biomedical Sciences Graduate Program, Ohio University, Athens, Ohio, USA
| | | | - Palwasha Khan
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA
- Translational Biomedical Sciences Graduate Program, Ohio University, Athens, Ohio, USA
| | - Ibiagbani M. Max-Harry
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA
- Molecular and Cellular Biology Graduate Program, Ohio University, Athens, Ohio, USA
| | - Amber M. Healy
- Department of Specialty Medicine, Ohio University, Athens, Ohio, USA
| | - Craig S. Nunemaker
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA
- Translational Biomedical Sciences Graduate Program, Ohio University, Athens, Ohio, USA
- Molecular and Cellular Biology Graduate Program, Ohio University, Athens, Ohio, USA
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Fuhri Snethlage CM, de Wit D, Wortelboer K, Rampanelli E, Hanssen NMJ, Nieuwdorp M. Can fecal microbiota transplantations modulate autoimmune responses in type 1 diabetes? Immunol Rev 2024; 325:46-63. [PMID: 38752578 DOI: 10.1111/imr.13345] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/22/2024]
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease targeting insulin-producing pancreatic beta cells. T1D is a multifactorial disease incorporating genetic and environmental factors. In recent years, the advances in high-throughput sequencing have allowed researchers to elucidate the changes in the gut microbiota taxonomy and functional capacity that accompany T1D development. An increasing number of studies have shown a role of the gut microbiota in mediating immune responses in health and disease, including autoimmunity. Fecal microbiota transplantations (FMT) have been largely used in murine models to prove a causal role of the gut microbiome in disease progression and have been shown to be a safe and effective treatment in inflammatory human diseases. In this review, we summarize and discuss recent research regarding the gut microbiota-host interactions in T1D, the current advancement in therapies for T1D, and the usefulness of FMT studies to explore microbiota-host immunity encounters in murine models and to shape the course of human type 1 diabetes.
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Affiliation(s)
- Coco M Fuhri Snethlage
- Department of Internal and Vascular Medicine, Amsterdam University Medical Center, Location AMC, Amsterdam, The Netherlands
| | - Douwe de Wit
- Department of Internal and Vascular Medicine, Amsterdam University Medical Center, Location AMC, Amsterdam, The Netherlands
| | - Koen Wortelboer
- Department of Internal and Vascular Medicine, Amsterdam University Medical Center, Location AMC, Amsterdam, The Netherlands
| | - Elena Rampanelli
- Department of Internal and Vascular Medicine, Amsterdam University Medical Center, Location AMC, Amsterdam, The Netherlands
- Amsterdam Institute for Infection and Immunity (AII), Amsterdam, The Netherlands
| | - Nordin M J Hanssen
- Department of Internal and Vascular Medicine, Amsterdam University Medical Center, Location AMC, Amsterdam, The Netherlands
- Amsterdam Diabeter Center, Amsterdam UMC, Amsterdam, The Netherlands
| | - Max Nieuwdorp
- Department of Internal and Vascular Medicine, Amsterdam University Medical Center, Location AMC, Amsterdam, The Netherlands
- Amsterdam Diabeter Center, Amsterdam UMC, Amsterdam, The Netherlands
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Lin C, Hu S, Cai X, Lv F, Yang W, Liu G, Yang X, Ji L. The opportunities and challenges of the disease-modifying immunotherapy for type 1 diabetes: A systematic review and meta-analysis. Pharmacol Res 2024; 203:107157. [PMID: 38531504 DOI: 10.1016/j.phrs.2024.107157] [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: 12/17/2023] [Revised: 03/22/2024] [Accepted: 03/22/2024] [Indexed: 03/28/2024]
Abstract
There are multiple disease-modifying immunotherapies showing the potential of preventing or delaying the progression of type 1 diabetes (T1D). We designed and performed this systematic review and meta-analysis to gain an overview of what a role immunotherapy plays in the treatment of T1D. We searched PubMed, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to December 2023. We included clinical trials of immunotherapy conducted in patients with T1D that reported the incidence of hypoglycemia or changes from baseline in at least one of following outcomes: 2 h and 4 h mixed-meal-stimulated C-peptide area under the curve (AUC), fasting C-peptide, daily insulin dosage, glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG). The results were computed as the weighted mean differences (WMDs) or odds ratios (ORs) and 95% confidence intervals (CIs) in random-effect model. In all, 34 clinical trials were included. When compared with control groups, 2 h C-peptide AUC was marginally higher in patient treated with nonantigen-based immunotherapies (WMD, 0.04nmol/L, 95% CI, 0.00-0.09 nmol/L, P=0.05), which was mainly driven by the effects of T cell-targeted therapy. A greater preservation in 4 h C-peptide AUC was observed in patients with nonantigen-based immunotherapies (WMD, 0.10nmol/L, 95% CI, 0.04-0.16 nmol/L, P=0.0007), which was mainly driven by the effects of tumor necrosis factor α (TNF-α) inhibitor and T cell-targeted therapy. After excluding small-sample trials, less daily insulin dosage was observed in patient treated with nonantigen-based immunotherapies when compared with control groups (WMD, -0.07units/kg/day, 95% CI, -0.11 to -0.03units/kg/day, P=0.0004). The use of antigen-based immunotherapies was also associated with a lower daily insulin dosage versus control groups (WMD, -0.11units/kg/day, 95% CI, -0.23 to -0.00units/kg/day, P=0.05). However, changes of HbA1c or FPG were comparable between nonantigen-based immunotherapies or antigen-based immunotherapies and control groups. The risk of hypoglycemia was not increased in patients treated with nonantigen-based immunotherapies or patients treated with antigen-based immunotherapies when compared with control groups. In conclusion, nonantigen-based immunotherapies were associated with a preservation of 2 h and 4 h C-peptide AUC in patients with T1D when compared with the controls, which was mainly driven by the effects of TNF-a inhibitor and T cell-targeted therapy. Both nonantigen-based immunotherapies and antigen-based immunotherapies tended to reduce the daily insulin dosage in patients with T1D when compared with the controls. However, they did not contribute to a substantial improvement in HbA1c or FPG. Both nonantigen-based immunotherapies and antigen-based immunotherapies were well tolerated with not increased risk of hypoglycemia in patients with T1D.
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Affiliation(s)
- Chu Lin
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Suiyuan Hu
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Xiaoling Cai
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China.
| | - Fang Lv
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Wenjia Yang
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Geling Liu
- Department of Endocrinology (Section I), Tangshan Gongren Hospital, Tangshan, Hebei, China
| | - Xiaolin Yang
- Department of Endocrinology (Section I), Tangshan Gongren Hospital, Tangshan, Hebei, China
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China.
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6
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Kennedy EC, Hawkes CP. Approaches to Measuring Beta Cell Reserve and Defining Partial Clinical Remission in Paediatric Type 1 Diabetes. CHILDREN (BASEL, SWITZERLAND) 2024; 11:186. [PMID: 38397298 PMCID: PMC10887271 DOI: 10.3390/children11020186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 01/26/2024] [Accepted: 02/01/2024] [Indexed: 02/25/2024]
Abstract
CONTEXT Type 1 diabetes (T1D) results from the autoimmune T-cell mediated destruction of pancreatic beta cells leading to insufficient insulin secretion. At the time of diagnosis of T1D, there is residual beta cell function that declines over the subsequent months to years. Recent interventions have been approved to preserve beta cell function in evolving T1D. OBJECTIVE The aim of this review is to summarise the approaches used to assess residual beta cell function in evolving T1D, and to highlight potential future directions. METHODS Studies including subjects aged 0 to 18 years were included in this review. The following search terms were used; "(type 1 diabetes) and (partial remission)" and "(type 1 diabetes) and (honeymoon)". References of included studies were reviewed to determine if additional relevant studies were eligible. RESULTS There are numerous approaches to quantifying beta cell reserve in evolving T1D. These include c-peptide measurement after a mixed meal or glucagon stimuli, fasting c-peptide, the urinary c-peptide/creatinine ratio, insulin dose-adjusted haemoglobin A1c, and other clinical models to estimate beta cell function. Other biomarkers may have a role, including the proinsulin/c-peptide ratio, cytokines, and microRNA. Studies using thresholds to determine if residual beta cell function is present often differ in values used to define remission. CONCLUSIONS As interventions are approved to preserve beta cell function, it will become increasingly necessary to quantify residual beta cell function in research and clinical contexts. In this report, we have highlighted the strengths and limitations of the current approaches.
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Affiliation(s)
- Elaine C Kennedy
- Department of Paediatrics and Child Health, University College Cork, T12 DC4A Cork, Ireland
- INFANT Research Centre, University College Cork, T12 DC4A Cork, Ireland
| | - Colin P Hawkes
- Department of Paediatrics and Child Health, University College Cork, T12 DC4A Cork, Ireland
- INFANT Research Centre, University College Cork, T12 DC4A Cork, Ireland
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
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Fanaropoulou NM, Tsatsani GC, Koufakis T, Kotsa K. Teplizumab: promises and challenges of a recently approved monoclonal antibody for the prevention of type 1 diabetes or preservation of residual beta cell function. Expert Rev Clin Immunol 2024; 20:185-196. [PMID: 37937833 DOI: 10.1080/1744666x.2023.2281990] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 11/07/2023] [Indexed: 11/09/2023]
Abstract
INTRODUCTION Type 1 diabetes (T1D) is a chronic autoimmune endocrinopathy with increasing incidence that results in the depletion of pancreatic beta cells and exogenous insulin dependence. Despite technological advances in insulin delivery, disease control remains suboptimal, while previous immunotherapy options have failed to prevent T1D. Recently, teplizumab, an immunomodulating monoclonal antibody, was approved to delay or prevent T1D. AREAS COVERED Five randomized controlled trials have tested different regimens of administration, mostly 14-day schemes with dose escalation. In participants with new-onset T1D, teplizumab delayed C-peptide decline, improved glycemic control, and reduced insulin demand for a median of 1 or 2 years. Studies in at-risk relatives of patients showed a decrease in T1D incidence during 2 years of follow-up. Subgroups of responders with unique metabolic and immunological characteristics were identified. Mild to moderate adverse effects were reported, including transient rash, cytopenia, nausea, vomiting, and infections. EXPERT OPINION Teplizumab marks a turning point in T1D therapy. Areas of future research include the ideal population for screening, cost-effectiveness, and challenges in treatment accessibility. More studies are essential to evaluate the ideal duration of the regimen, the potential benefit of combinations with other drugs, and to identify endophenotypes with a high probability of response.
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Affiliation(s)
- Nina Maria Fanaropoulou
- School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Georgia C Tsatsani
- School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Theocharis Koufakis
- Second Propaedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Kalliopi Kotsa
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
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Ramos EL, Dayan CM, Chatenoud L, Sumnik Z, Simmons KM, Szypowska A, Gitelman SE, Knecht LA, Niemoeller E, Tian W, Herold KC. Teplizumab and β-Cell Function in Newly Diagnosed Type 1 Diabetes. N Engl J Med 2023; 389:2151-2161. [PMID: 37861217 DOI: 10.1056/nejmoa2308743] [Citation(s) in RCA: 89] [Impact Index Per Article: 44.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2023]
Abstract
BACKGROUND Teplizumab, a humanized monoclonal antibody to CD3 on T cells, is approved by the Food and Drug Administration to delay the onset of clinical type 1 diabetes (stage 3) in patients 8 years of age or older with preclinical (stage 2) disease. Whether treatment with intravenous teplizumab in patients with newly diagnosed type 1 diabetes can prevent disease progression is unknown. METHODS In this phase 3, randomized, placebo-controlled trial, we assessed β-cell preservation, clinical end points, and safety in children and adolescents who were assigned to receive teplizumab or placebo for two 12-day courses. The primary end point was the change from baseline in β-cell function, as measured by stimulated C-peptide levels at week 78. The key secondary end points were the insulin doses that were required to meet glycemic goals, glycated hemoglobin levels, time in the target glucose range, and clinically important hypoglycemic events. RESULTS Patients treated with teplizumab (217 patients) had significantly higher stimulated C-peptide levels than patients receiving placebo (111 patients) at week 78 (least-squares mean difference, 0.13 pmol per milliliter; 95% confidence interval [CI], 0.09 to 0.17; P<0.001), and 94.9% (95% CI, 89.5 to 97.6) of patients treated with teplizumab maintained a clinically meaningful peak C-peptide level of 0.2 pmol per milliliter or greater, as compared with 79.2% (95% CI, 67.7 to 87.4) of those receiving placebo. The groups did not differ significantly with regard to the key secondary end points. Adverse events occurred primarily in association with administration of teplizumab or placebo and included headache, gastrointestinal symptoms, rash, lymphopenia, and mild cytokine release syndrome. CONCLUSIONS Two 12-day courses of teplizumab in children and adolescents with newly diagnosed type 1 diabetes showed benefit with respect to the primary end point of preservation of β-cell function, but no significant differences between the groups were observed with respect to the secondary end points. (Funded by Provention Bio and Sanofi; PROTECT ClinicalTrials.gov number, NCT03875729.).
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Affiliation(s)
- Eleanor L Ramos
- From Provention Bio, a Sanofi company, Red Bank, NJ (E.L.R., L.A.K., W.T.); Cardiff University, Cardiff, United Kingdom (C.M.D.); Université Paris Cité, CNRS, INSERM, Institut Necker Enfants Malades-INEM, Paris (L.C.); the Department of Pediatrics, Motol University Hospital, Second Faculty of Medicine-Charles University, Prague, Czech Republic (Z.S.); the Barbara Davis Center for Diabetes/University of Colorado School of Medicine, Aurora (K.M.S.); the Medical University of Warsaw, Warsaw, Poland (A.S.); the University of California, San Francisco, San Francisco (S.E.G.); Sanofi, Frankfurt, Germany (E.N.); and the Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT (K.C.H.)
| | - Colin M Dayan
- From Provention Bio, a Sanofi company, Red Bank, NJ (E.L.R., L.A.K., W.T.); Cardiff University, Cardiff, United Kingdom (C.M.D.); Université Paris Cité, CNRS, INSERM, Institut Necker Enfants Malades-INEM, Paris (L.C.); the Department of Pediatrics, Motol University Hospital, Second Faculty of Medicine-Charles University, Prague, Czech Republic (Z.S.); the Barbara Davis Center for Diabetes/University of Colorado School of Medicine, Aurora (K.M.S.); the Medical University of Warsaw, Warsaw, Poland (A.S.); the University of California, San Francisco, San Francisco (S.E.G.); Sanofi, Frankfurt, Germany (E.N.); and the Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT (K.C.H.)
| | - Lucienne Chatenoud
- From Provention Bio, a Sanofi company, Red Bank, NJ (E.L.R., L.A.K., W.T.); Cardiff University, Cardiff, United Kingdom (C.M.D.); Université Paris Cité, CNRS, INSERM, Institut Necker Enfants Malades-INEM, Paris (L.C.); the Department of Pediatrics, Motol University Hospital, Second Faculty of Medicine-Charles University, Prague, Czech Republic (Z.S.); the Barbara Davis Center for Diabetes/University of Colorado School of Medicine, Aurora (K.M.S.); the Medical University of Warsaw, Warsaw, Poland (A.S.); the University of California, San Francisco, San Francisco (S.E.G.); Sanofi, Frankfurt, Germany (E.N.); and the Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT (K.C.H.)
| | - Zdenek Sumnik
- From Provention Bio, a Sanofi company, Red Bank, NJ (E.L.R., L.A.K., W.T.); Cardiff University, Cardiff, United Kingdom (C.M.D.); Université Paris Cité, CNRS, INSERM, Institut Necker Enfants Malades-INEM, Paris (L.C.); the Department of Pediatrics, Motol University Hospital, Second Faculty of Medicine-Charles University, Prague, Czech Republic (Z.S.); the Barbara Davis Center for Diabetes/University of Colorado School of Medicine, Aurora (K.M.S.); the Medical University of Warsaw, Warsaw, Poland (A.S.); the University of California, San Francisco, San Francisco (S.E.G.); Sanofi, Frankfurt, Germany (E.N.); and the Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT (K.C.H.)
| | - Kimber M Simmons
- From Provention Bio, a Sanofi company, Red Bank, NJ (E.L.R., L.A.K., W.T.); Cardiff University, Cardiff, United Kingdom (C.M.D.); Université Paris Cité, CNRS, INSERM, Institut Necker Enfants Malades-INEM, Paris (L.C.); the Department of Pediatrics, Motol University Hospital, Second Faculty of Medicine-Charles University, Prague, Czech Republic (Z.S.); the Barbara Davis Center for Diabetes/University of Colorado School of Medicine, Aurora (K.M.S.); the Medical University of Warsaw, Warsaw, Poland (A.S.); the University of California, San Francisco, San Francisco (S.E.G.); Sanofi, Frankfurt, Germany (E.N.); and the Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT (K.C.H.)
| | - Agnieszka Szypowska
- From Provention Bio, a Sanofi company, Red Bank, NJ (E.L.R., L.A.K., W.T.); Cardiff University, Cardiff, United Kingdom (C.M.D.); Université Paris Cité, CNRS, INSERM, Institut Necker Enfants Malades-INEM, Paris (L.C.); the Department of Pediatrics, Motol University Hospital, Second Faculty of Medicine-Charles University, Prague, Czech Republic (Z.S.); the Barbara Davis Center for Diabetes/University of Colorado School of Medicine, Aurora (K.M.S.); the Medical University of Warsaw, Warsaw, Poland (A.S.); the University of California, San Francisco, San Francisco (S.E.G.); Sanofi, Frankfurt, Germany (E.N.); and the Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT (K.C.H.)
| | - Stephen E Gitelman
- From Provention Bio, a Sanofi company, Red Bank, NJ (E.L.R., L.A.K., W.T.); Cardiff University, Cardiff, United Kingdom (C.M.D.); Université Paris Cité, CNRS, INSERM, Institut Necker Enfants Malades-INEM, Paris (L.C.); the Department of Pediatrics, Motol University Hospital, Second Faculty of Medicine-Charles University, Prague, Czech Republic (Z.S.); the Barbara Davis Center for Diabetes/University of Colorado School of Medicine, Aurora (K.M.S.); the Medical University of Warsaw, Warsaw, Poland (A.S.); the University of California, San Francisco, San Francisco (S.E.G.); Sanofi, Frankfurt, Germany (E.N.); and the Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT (K.C.H.)
| | - Laura A Knecht
- From Provention Bio, a Sanofi company, Red Bank, NJ (E.L.R., L.A.K., W.T.); Cardiff University, Cardiff, United Kingdom (C.M.D.); Université Paris Cité, CNRS, INSERM, Institut Necker Enfants Malades-INEM, Paris (L.C.); the Department of Pediatrics, Motol University Hospital, Second Faculty of Medicine-Charles University, Prague, Czech Republic (Z.S.); the Barbara Davis Center for Diabetes/University of Colorado School of Medicine, Aurora (K.M.S.); the Medical University of Warsaw, Warsaw, Poland (A.S.); the University of California, San Francisco, San Francisco (S.E.G.); Sanofi, Frankfurt, Germany (E.N.); and the Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT (K.C.H.)
| | - Elisabeth Niemoeller
- From Provention Bio, a Sanofi company, Red Bank, NJ (E.L.R., L.A.K., W.T.); Cardiff University, Cardiff, United Kingdom (C.M.D.); Université Paris Cité, CNRS, INSERM, Institut Necker Enfants Malades-INEM, Paris (L.C.); the Department of Pediatrics, Motol University Hospital, Second Faculty of Medicine-Charles University, Prague, Czech Republic (Z.S.); the Barbara Davis Center for Diabetes/University of Colorado School of Medicine, Aurora (K.M.S.); the Medical University of Warsaw, Warsaw, Poland (A.S.); the University of California, San Francisco, San Francisco (S.E.G.); Sanofi, Frankfurt, Germany (E.N.); and the Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT (K.C.H.)
| | - Wei Tian
- From Provention Bio, a Sanofi company, Red Bank, NJ (E.L.R., L.A.K., W.T.); Cardiff University, Cardiff, United Kingdom (C.M.D.); Université Paris Cité, CNRS, INSERM, Institut Necker Enfants Malades-INEM, Paris (L.C.); the Department of Pediatrics, Motol University Hospital, Second Faculty of Medicine-Charles University, Prague, Czech Republic (Z.S.); the Barbara Davis Center for Diabetes/University of Colorado School of Medicine, Aurora (K.M.S.); the Medical University of Warsaw, Warsaw, Poland (A.S.); the University of California, San Francisco, San Francisco (S.E.G.); Sanofi, Frankfurt, Germany (E.N.); and the Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT (K.C.H.)
| | - Kevan C Herold
- From Provention Bio, a Sanofi company, Red Bank, NJ (E.L.R., L.A.K., W.T.); Cardiff University, Cardiff, United Kingdom (C.M.D.); Université Paris Cité, CNRS, INSERM, Institut Necker Enfants Malades-INEM, Paris (L.C.); the Department of Pediatrics, Motol University Hospital, Second Faculty of Medicine-Charles University, Prague, Czech Republic (Z.S.); the Barbara Davis Center for Diabetes/University of Colorado School of Medicine, Aurora (K.M.S.); the Medical University of Warsaw, Warsaw, Poland (A.S.); the University of California, San Francisco, San Francisco (S.E.G.); Sanofi, Frankfurt, Germany (E.N.); and the Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT (K.C.H.)
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9
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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
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10
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Pande AK, Dutta D, Singla R. Prevention of Type 1 Diabetes: Current Perspective. Indian J Endocrinol Metab 2023; 27:277-285. [PMID: 37867976 PMCID: PMC10586562 DOI: 10.4103/ijem.ijem_78_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 04/17/2023] [Accepted: 05/16/2023] [Indexed: 10/24/2023] Open
Abstract
People living with type 1 Diabetes (T1D) and their families have poor perception of health related quality of life. Therapies for T1D are becoming better with time, but they still involve a lot of effort. Prevention of T1D, if successful, has potential to change lives of millions of families across the globe. Type 1 diabetes is an autoimmune disease with underlying genetic predisposition for autoimmunity against beta cell antigens upon exposure to an environmental trigger. Identifying underlying primary antigen responsible for initiating autoimmune cascade, avoiding environmental trigger and modifying immunity has all been used as strategies for preventing or delaying onset of type 1 diabetes. Primary prevention for type 1 diabetes is hindered by difficulty in identifying at-risk population and also due to lack of effective preventive strategy. Secondary prevention, in children with presence of autoimmunity, has recently received a boost with approval of Teplizumab, an immunity modifying drug by its Anti-CD3 action. Application of preventive strategies would also change based on country specific incidence, prevalence and availability of health resources. In current review, an update on preventive strategies for type 1 diabetes is being discussed as well as their applicability in Indian context.
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Affiliation(s)
- Arun K Pande
- Consultant Endocrinologist, Lucknow Endocrine Diabetes and Thyroid Clinic, Lucknow, Uttar Pradesh, India
| | - Deep Dutta
- Consultant Endocrinologist, CEDAR Superspeciality Healthcare, Dwarka, New Delhi, India
| | - Rajiv Singla
- Consultant Endocrinologist, Kalpavriksh Healthcare, Dwarka, Delhi, India
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11
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Du C, Whiddett RO, Buckle I, Chen C, Forbes JM, Fotheringham AK. Advanced Glycation End Products and Inflammation in Type 1 Diabetes Development. Cells 2022; 11:3503. [PMID: 36359899 PMCID: PMC9657002 DOI: 10.3390/cells11213503] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 10/18/2022] [Accepted: 10/31/2022] [Indexed: 08/08/2023] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease in which the β-cells of the pancreas are attacked by the host's immune system, ultimately resulting in hyperglycemia. It is a complex multifactorial disease postulated to result from a combination of genetic and environmental factors. In parallel with increasing prevalence of T1D in genetically stable populations, highlighting an environmental component, consumption of advanced glycation end products (AGEs) commonly found in in Western diets has increased significantly over the past decades. AGEs can bind to cell surface receptors including the receptor for advanced glycation end products (RAGE). RAGE has proinflammatory roles including in host-pathogen defense, thereby influencing immune cell behavior and can activate and cause proliferation of immune cells such as islet infiltrating CD8+ and CD4+ T cells and suppress the activity of T regulatory cells, contributing to β-cell injury and hyperglycemia. Insights from studies of individuals at risk of T1D have demonstrated that progression to symptomatic onset and diagnosis can vary, ranging from months to years, providing a window of opportunity for prevention strategies. Interaction between AGEs and RAGE is believed to be a major environmental risk factor for T1D and targeting the AGE-RAGE axis may act as a potential therapeutic strategy for T1D prevention.
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Affiliation(s)
- Chenping Du
- Glycation and Diabetes Complications Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba 4102, Australia
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia 4072, Australia
| | - Rani O. Whiddett
- Glycation and Diabetes Complications Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba 4102, Australia
| | - Irina Buckle
- Glycation and Diabetes Complications Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba 4102, Australia
- Faculty of Medicine, The University of Queensland, St Lucia 4072, Australia
| | - Chen Chen
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia 4072, Australia
| | - Josephine M. Forbes
- Glycation and Diabetes Complications Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba 4102, Australia
- Faculty of Medicine, The University of Queensland, St Lucia 4072, Australia
- Department of Medicine, The University of Melbourne, Austin Health, Heidelberg 3084, Australia
| | - Amelia K. Fotheringham
- Glycation and Diabetes Complications Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba 4102, Australia
- Faculty of Medicine, The University of Queensland, St Lucia 4072, Australia
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12
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Nagy G, Szekely TE, Somogyi A, Herold M, Herold Z. New therapeutic approaches for type 1 diabetes: Disease-modifying therapies. World J Diabetes 2022; 13:835-850. [PMID: 36312000 PMCID: PMC9606789 DOI: 10.4239/wjd.v13.i10.835] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 08/08/2022] [Accepted: 09/15/2022] [Indexed: 02/05/2023] Open
Abstract
It has been 100 years since the first successful clinical use of insulin, yet it remains the only treatment option for type 1 diabetes mellitus (T1DM) patients. Advances in diabetes care, such as insulin analogue therapies and new devices, including continuous glucose monitoring with continuous subcutaneous insulin infusion have improved the quality of life of patients but have no impact on the pathogenesis of the disease. They do not eliminate long-term complications and require several lifestyle sacrifices. A more ideal future therapy for T1DM, instead of supplementing the insufficient hormone production (a consequence of β-cell destruction), would also aim to stop or slow down the destructive autoimmune process. The discovery of the autoimmune nature of type 1 diabetes mellitus has presented several targets by which disease progression may be altered. The goal of disease-modifying therapies is to target autoimmune mechanisms and prevent β-cell destruction. T1DM patients with better β-cell function have better glycemic control, reduced incidence of long-term complications and hypoglycemic episodes. Unfortunately, at the time symptomatic T1DM is diagnosed, most of the insulin secreting β cells are usually lost. Therefore, to maximize the salvageable β-cell mass by disease-modifying therapies, detecting autoimmune markers in an early, optimally presymptomatic phase of T1DM is of great importance. Disease-modifying therapies, such as immuno- and regenerative therapies are expected to take a relevant place in diabetology. The aim of this article was to provide a brief insight into the pathogenesis and course of T1DM and present the current state of disease-modifying therapeutic interventions that may impact future diabetes treatment.
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Affiliation(s)
- Geza Nagy
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest H-1088, Hungary
| | - Tekla Evelin Szekely
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest H-1088, Hungary
| | - Aniko Somogyi
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest H-1088, Hungary
| | - Magdolna Herold
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest H-1088, Hungary
| | - Zoltan Herold
- Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, Budapest H-1083, Hungary
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13
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Lunati ME, Fiorina P. Antigen-based Immunotherapy Improves Glycemic Metrics and β-Cell Function. J Clin Endocrinol Metab 2022; 107:e4250-e4251. [PMID: 35881553 DOI: 10.1210/clinem/dgac437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Indexed: 11/19/2022]
Affiliation(s)
| | - Paolo Fiorina
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy
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14
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CCL21 and beta-cell antigen releasing hydrogels as tolerance-inducing therapy in Type I diabetes. J Control Release 2022; 348:499-517. [PMID: 35691500 DOI: 10.1016/j.jconrel.2022.06.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 05/25/2022] [Accepted: 06/06/2022] [Indexed: 11/20/2022]
Abstract
Type-I Diabetes (T1D) is caused by defective immunotolerance mechanisms enabling autoreactive T cells to escape regulation in lymphoid organs and destroy insulin-producing β-cells in the pancreas, leading to insulin dependence. Strategies to promote β-cell tolerance could arrest T1D. We previously showed that secretion of secondary lymphoid chemokine CCL21 by CCL21 transgenic β-cells induced tolerance and protected non-obese diabetic (NOD) mice from T1D. T1D protection was associated with formation of lymph node-like stromal networks containing tolerogenic fibroblastic reticular cells (FRCs). Here, we developed a polyethylene glycol (PEG) hydrogel platform with hydrolytically degradable PEG-diester dithiol crosslinkers to provide controlled and sustained delivery of CCL21 and β-cell antigens for at least 28 days in vitro and recapitulate properties associated with the tolerogenic environment of CCL21 transgenic β-cells in our previous studies. CCL21 and MHC-II restricted antigens were tethered to gels via simple click-chemistry while MHC-I restricted antigens were loaded in PEG-based polymeric nanovesicles and incorporated in the gel networks. CCL21 and antigen release kinetics depended on the PEG gel tethering strategy and the linkers. Importantly, in vitro functionality, chemotaxis, and activation of antigen-specific T cells were preserved. Implantation of CCL21 and β-cell antigen gels under the kidney capsule of pre-diabetic NOD mice led to enrichment of adoptively transferred antigen-specific T cells, formation of gp38 + FRC-like stromal cell networks, and increased regulation of specific T cells with reduced accumulation within pancreatic islets. Thus, our platform for sustained release of β-cell antigens and CCL21 immunomodulatory molecule could enable the development of antigen-specific tolerance therapies for T1D.
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15
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Liu YF, Powrie J, Arif S, Yang JH, Williams E, Khatri L, Joshi M, Lhuillier L, Fountoulakis N, Smith E, Beam C, Lorenc A, Peakman M, Tree T. Immune and Metabolic Effects of Antigen-Specific Immunotherapy Using Multiple β-Cell Peptides in Type 1 Diabetes. Diabetes 2022; 71:722-732. [PMID: 35073398 PMCID: PMC8965665 DOI: 10.2337/db21-0728] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 01/15/2022] [Indexed: 01/11/2023]
Abstract
Type 1 diabetes is characterized by a loss of tolerance to pancreatic β-cell autoantigens and defects in regulatory T-cell (Treg) function. In preclinical models, immunotherapy with MHC-selective, autoantigenic peptides restores immune tolerance, prevents diabetes, and shows greater potency when multiple peptides are used. To translate this strategy into the clinical setting, we administered a mixture of six HLA-DRB1*0401-selective, β-cell peptides intradermally to patients with recent-onset type 1 diabetes possessing this genotype in a randomized placebo-controlled study at monthly doses of 10, 100, and 500 μg for 24 weeks. Stimulated C-peptide (measuring insulin functional reserve) had declined in all placebo subjects at 24 weeks but was maintained at ≥100% baseline levels in one-half of the treated group. Treatment was accompanied by significant changes in islet-specific immune responses and a dose-dependent increase in Treg expression of the canonical transcription factor FOXP3 and changes in Treg gene expression. In this first-in-human study, multiple-peptide immunotherapy shows promise as a strategy to correct immune regulatory defects fundamental to the pathobiology of autoimmune diabetes.
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Affiliation(s)
- Yuk-Fun Liu
- Department of Diabetes, School of Life Course Sciences, King’s College London, London, U.K
- Department of Diabetes and Endocrinology, Guy’s and St. Thomas’ NHS Foundation Trust, London, U.K
- Institute of Diabetes, Endocrinology and Obesity, King’s Health Partners, London, U.K
| | - Jake Powrie
- Department of Diabetes and Endocrinology, Guy’s and St. Thomas’ NHS Foundation Trust, London, U.K
| | - Sefina Arif
- Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College London, London, U.K
| | - Jennie H.M. Yang
- Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College London, London, U.K
- National Institute for Health Research Biomedical Research Centre, Guy’s and St. Thomas’ NHS Foundation Trust and Kings College London, London, U.K
| | - Evangelia Williams
- Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College London, London, U.K
- National Institute for Health Research Biomedical Research Centre, Guy’s and St. Thomas’ NHS Foundation Trust and Kings College London, London, U.K
| | - Leena Khatri
- Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College London, London, U.K
- National Institute for Health Research Biomedical Research Centre, Guy’s and St. Thomas’ NHS Foundation Trust and Kings College London, London, U.K
| | - Mamta Joshi
- Department of Diabetes and Endocrinology, Guy’s and St. Thomas’ NHS Foundation Trust, London, U.K
| | - Loic Lhuillier
- Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College London, London, U.K
| | - Nikolaos Fountoulakis
- Department of Diabetes and Endocrinology, Guy’s and St. Thomas’ NHS Foundation Trust, London, U.K
| | | | - Craig Beam
- Department of Biomedical Sciences, Homer Stryker MD School of Medicine, Western Michigan University, Kalamazoo, MI
| | - Anna Lorenc
- Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College London, London, U.K
| | - Mark Peakman
- Department of Diabetes, School of Life Course Sciences, King’s College London, London, U.K
- Department of Diabetes and Endocrinology, Guy’s and St. Thomas’ NHS Foundation Trust, London, U.K
- Institute of Diabetes, Endocrinology and Obesity, King’s Health Partners, London, U.K
- Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College London, London, U.K
- Corresponding authors: Mark Peakman, , and Timothy Tree,
| | - Timothy Tree
- Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College London, London, U.K
- National Institute for Health Research Biomedical Research Centre, Guy’s and St. Thomas’ NHS Foundation Trust and Kings College London, London, U.K
- Corresponding authors: Mark Peakman, , and Timothy Tree,
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16
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Wilhelm-Benartzi CS, Miller SE, Bruggraber S, Picton D, Wilson M, Gatley K, Chhabra A, Marcovecchio ML, Hendriks AEJ, Morobé H, Chmura PJ, Bond S, Aschemeier-Fuchs B, Knip M, Tree T, Overbergh L, Pall J, Arnaud O, Haller MJ, Nitsche A, Schulte AM, Mathieu C, Mander A, Dunger D. Study protocol: Minimum effective low dose: anti-human thymocyte globulin (MELD-ATG): phase II, dose ranging, efficacy study of antithymocyte globulin (ATG) within 6 weeks of diagnosis of type 1 diabetes. BMJ Open 2021; 11:e053669. [PMID: 34876434 PMCID: PMC8655536 DOI: 10.1136/bmjopen-2021-053669] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
INTRODUCTION Type 1 diabetes (T1D) is a chronic autoimmune disease, characterised by progressive destruction of the insulin-producing β cells of the pancreas. One immunosuppressive agent that has recently shown promise in the treatment of new-onset T1D subjects aged 12-45 years is antithymocyte globulin (ATG), Thymoglobuline, encouraging further exploration in lower age groups. METHODS AND ANALYSIS Minimal effective low dose (MELD)-ATG is a phase 2, multicentre, randomised, double-blind, placebo-controlled, multiarm parallel-group trial in participants 5-25 years diagnosed with T1D within 3-9 weeks of planned treatment day 1. A total of 114 participants will be recruited sequentially into seven different cohorts with the first cohort of 30 participants being randomised to placebo, 2.5 mg/kg, 1.5 mg/kg, 0.5 mg/kg and 0.1 mg/kg ATG total dose in a 1:1:1:1:1 allocation ratio. The next six cohorts of 12-15 participants will be randomised to placebo, 2.5 mg/kg, and one or two selected middle ATG total doses in a 1:1:1:1 or 1:1:1 allocation ratio, as dependent on the number of middle doses, given intravenously over two consecutive days. The primary objective will be to determine the changes in stimulated C-peptide response over the first 2 hours of a mixed meal tolerance test at 12 months for 2.5 mg/kg ATG arm vs the placebo. Conditional on finding a significant difference at 2.5 mg/kg, a minimally effective dose will be sought. Secondary objectives include the determination of the effects of a particular ATG treatment dose on (1) stimulated C-peptide, (2) glycated haemoglobin, (3) daily insulin dose, (4) time in range by intermittent continuous glucose monitoring measures, (5) fasting and stimulated dry blood spot (DBS) C-peptide measurements. ETHICS AND DISSEMINATION MELD-ATG received first regulatory and ethical approvals in Belgium in September 2020 and from the German and UK regulators as of February 2021. The publication policy is set in the INNODIA (An innovative approach towards understanding and arresting Type 1 diabetes consortium) grant agreement (www.innodia.eu). TRIAL REGISTRATION NUMBER NCT03936634; Pre-results.
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Affiliation(s)
| | - Sarah E Miller
- Department of Paediatrics, University of Cambridge, Cambridge, UK
- Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | | | - Diane Picton
- Department of Paediatrics, University of Cambridge, Cambridge, UK
| | - Mark Wilson
- Department of Paediatrics, University of Cambridge, Cambridge, UK
| | - Katrina Gatley
- Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Anita Chhabra
- Pharmacy, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | | | | | - Hilde Morobé
- Katholieke Universiteit Leuven/ Universitaire Ziekenhuizen, Leuven, Belgium
| | - Piotr Jaroslaw Chmura
- Center for Protein Research, Kobenhavns Universitet Sundhedsvidenskabelige Fakultet, Kobenhavn, Denmark
| | - Simon Bond
- Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Bärbel Aschemeier-Fuchs
- Diabetes Centre for Children and Adolescents, Children's Hospital Auf der Bult, Hannover, Germany
| | - Mikael Knip
- Research Program for Clinical and Molecular Metabolism, University of Helsinki Faculty of Medicine, Helsinki, Finland
- Pediatric Research Centre, University of Helsinki Children's Hospital, Helsinki, Finland
| | - Timothy Tree
- Department of Immunobiology, King's College London, London, UK
| | - Lut Overbergh
- Katholieke Universiteit Leuven/ Universitaire Ziekenhuizen, Leuven, Belgium
| | - Jaivier Pall
- INNODIA Patient Advisory Committee, Madrid, Spain
| | | | - Michael J Haller
- Department of Pediatrics, University of Florida, Gainesville, Florida, USA
| | | | | | - Chantal Mathieu
- Katholieke Universiteit Leuven/ Universitaire Ziekenhuizen, Leuven, Belgium
| | - Adrian Mander
- Centre for Trials Research, College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK
| | - David Dunger
- Department of Paediatrics, University of Cambridge, Cambridge, UK
- Wellcome Trust-MRC Institute of Metabolic Science, Cambridge University, Cambridge, UK
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17
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Ramzy A, Thompson DM, Ward-Hartstonge KA, Ivison S, Cook L, Garcia RV, Loyal J, Kim PTW, Warnock GL, Levings MK, Kieffer TJ. Implanted pluripotent stem-cell-derived pancreatic endoderm cells secrete glucose-responsive C-peptide in patients with type 1 diabetes. Cell Stem Cell 2021; 28:2047-2061.e5. [PMID: 34861146 DOI: 10.1016/j.stem.2021.10.003] [Citation(s) in RCA: 185] [Impact Index Per Article: 46.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 04/29/2021] [Accepted: 10/08/2021] [Indexed: 12/11/2022]
Abstract
An open-label, first-in-human phase 1/2 study is being conducted to evaluate the safety and efficacy of pancreatic endoderm cells (PECs) implanted in non-immunoprotective macroencapsulation devices for the treatment of type 1 diabetes. We report an analysis on 1 year of data from the first cohort of 15 patients from a single trial site that received subcutaneous implantation of cell products combined with an immunosuppressive regimen. Implants were well tolerated with no teratoma formation or severe graft-related adverse events. After implantation, patients had increased fasting C-peptide levels and increased glucose-responsive C-peptide levels and developed mixed meal-stimulated C-peptide secretion. There were immunosuppression-related transient increases in circulating regulatory T cells, PD1high T cells, and IL17A+CD4+ T cells. Explanted grafts contained cells with a mature β cell phenotype that were immunoreactive for insulin, islet amyloid polypeptide, and MAFA. These data, and associated findings (Shapiro et al., 2021), are the first reported evidence of meal-regulated insulin secretion by differentiated stem cells in patients.
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Affiliation(s)
- Adam Ramzy
- Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - David M Thompson
- Division of Endocrinology, Department of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Kirsten A Ward-Hartstonge
- Department of Surgery, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; BC Children's Hospital Research Institute (BCCHRI), Vancouver, BC V5Z 4H4, Canada
| | - Sabine Ivison
- Department of Surgery, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; BC Children's Hospital Research Institute (BCCHRI), Vancouver, BC V5Z 4H4, Canada
| | - Laura Cook
- Department of Surgery, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; BC Children's Hospital Research Institute (BCCHRI), Vancouver, BC V5Z 4H4, Canada
| | - Rosa V Garcia
- Department of Surgery, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; BC Children's Hospital Research Institute (BCCHRI), Vancouver, BC V5Z 4H4, Canada
| | - Jackson Loyal
- Division of Endocrinology, Department of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Peter T W Kim
- Department of Surgery, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Garth L Warnock
- Department of Surgery, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Megan K Levings
- Department of Surgery, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; BC Children's Hospital Research Institute (BCCHRI), Vancouver, BC V5Z 4H4, Canada; School of Biomedical Engineering, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Timothy J Kieffer
- Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Department of Surgery, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; School of Biomedical Engineering, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
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Guerra JVS, Dias MMG, Brilhante AJVC, Terra MF, García-Arévalo M, Figueira ACM. Multifactorial Basis and Therapeutic Strategies in Metabolism-Related Diseases. Nutrients 2021; 13:nu13082830. [PMID: 34444990 PMCID: PMC8398524 DOI: 10.3390/nu13082830] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 08/09/2021] [Accepted: 08/11/2021] [Indexed: 12/11/2022] Open
Abstract
Throughout the 20th and 21st centuries, the incidence of non-communicable diseases (NCDs), also known as chronic diseases, has been increasing worldwide. Changes in dietary and physical activity patterns, along with genetic conditions, are the main factors that modulate the metabolism of individuals, leading to the development of NCDs. Obesity, diabetes, metabolic associated fatty liver disease (MAFLD), and cardiovascular diseases (CVDs) are classified in this group of chronic diseases. Therefore, understanding the underlying molecular mechanisms of these diseases leads us to develop more accurate and effective treatments to reduce or mitigate their prevalence in the population. Given the global relevance of NCDs and ongoing research progress, this article reviews the current understanding about NCDs and their related risk factors, with a focus on obesity, diabetes, MAFLD, and CVDs, summarizing the knowledge about their pathophysiology and highlighting the currently available and emerging therapeutic strategies, especially pharmacological interventions. All of these diseases play an important role in the contamination by the SARS-CoV-2 virus, as well as in the progression and severity of the symptoms of the coronavirus disease 2019 (COVID-19). Therefore, we briefly explore the relationship between NCDs and COVID-19.
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Affiliation(s)
- João V. S. Guerra
- Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biosciences National Laboratory (LNBio), Polo II de Alta Tecnologia—R. Giuseppe Máximo Scolfaro, Campinas 13083-100, Brazil; (J.V.S.G.); (M.M.G.D.); (M.F.T.)
- Graduate Program in Pharmaceutical Sciences, Faculty Pharmaceutical Sciences, University of Campinas, Campinas 13083-970, Brazil
| | - Marieli M. G. Dias
- Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biosciences National Laboratory (LNBio), Polo II de Alta Tecnologia—R. Giuseppe Máximo Scolfaro, Campinas 13083-100, Brazil; (J.V.S.G.); (M.M.G.D.); (M.F.T.)
- Graduate Program in Functional and Molecular Biology, Institute of Biology, State University of Campinas (Unicamp), Campinas 13083-970, Brazil;
| | - Anna J. V. C. Brilhante
- Graduate Program in Functional and Molecular Biology, Institute of Biology, State University of Campinas (Unicamp), Campinas 13083-970, Brazil;
- Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biorenewables National Laboratory (LNBR), Polo II de Alta Tecnologia—R. Giuseppe Máximo Scolfaro, Campinas 13083-100, Brazil
| | - Maiara F. Terra
- Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biosciences National Laboratory (LNBio), Polo II de Alta Tecnologia—R. Giuseppe Máximo Scolfaro, Campinas 13083-100, Brazil; (J.V.S.G.); (M.M.G.D.); (M.F.T.)
- Graduate Program in Functional and Molecular Biology, Institute of Biology, State University of Campinas (Unicamp), Campinas 13083-970, Brazil;
| | - Marta García-Arévalo
- Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biosciences National Laboratory (LNBio), Polo II de Alta Tecnologia—R. Giuseppe Máximo Scolfaro, Campinas 13083-100, Brazil; (J.V.S.G.); (M.M.G.D.); (M.F.T.)
- Correspondence: or (M.G.-A.); (A.C.M.F.)
| | - Ana Carolina M. Figueira
- Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biosciences National Laboratory (LNBio), Polo II de Alta Tecnologia—R. Giuseppe Máximo Scolfaro, Campinas 13083-100, Brazil; (J.V.S.G.); (M.M.G.D.); (M.F.T.)
- Correspondence: or (M.G.-A.); (A.C.M.F.)
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Ramzy A, Kieffer TJ. Altered islet prohormone processing: A cause or consequence of diabetes? Physiol Rev 2021; 102:155-208. [PMID: 34280055 DOI: 10.1152/physrev.00008.2021] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Peptide hormones are first produced as larger precursor prohormones that require endoproteolytic cleavage to liberate the mature hormones. A structurally conserved but functionally distinct family of nine prohormone convertase enzymes (PCs) are responsible for cleavage of protein precursors of which PC1/3 and PC2 are known to be exclusive to neuroendocrine cells and responsible for prohormone cleavage. Differential expression of PCs within tissues define prohormone processing; whereas glucagon is the major product liberated from proglucagon via PC2 in pancreatic α-cells, proglucagon is preferentially processed by PC1/3 in intestinal L cells to produce glucagon-like peptides 1 and 2 (GLP-1, GLP-2). Beyond our understanding of processing of islet prohormones in healthy islets, there is convincing evidence that proinsulin, proIAPP, and proglucagon processing is altered during prediabetes and diabetes. There is predictive value of elevated circulating proinsulin or proinsulin : C-peptide ratio for progression to type 2 diabetes and elevated proinsulin or proinsulin : C-peptide is predictive for development of type 1 diabetes in at risk groups. After onset of diabetes, patients have elevated circulating proinsulin and proIAPP and proinsulin may be an autoantigen in type 1 diabetes. Further, preclinical studies reveal that α-cells have altered proglucagon processing during diabetes leading to increased GLP-1 production. We conclude that despite strong associative data, current evidence is inconclusive on the potential causal role of impaired prohormone processing in diabetes, and suggest that future work should focus on resolving the question of whether altered prohormone processing is a causal driver or merely a consequence of diabetes pathology.
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Affiliation(s)
- Adam Ramzy
- Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - Timothy J Kieffer
- Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.,Department of Surgery, University of British Columbia, Vancouver, BC, Canada.,School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada
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Sims EK, Carr ALJ, Oram RA, DiMeglio LA, Evans-Molina C. 100 years of insulin: celebrating the past, present and future of diabetes therapy. Nat Med 2021; 27:1154-1164. [PMID: 34267380 PMCID: PMC8802620 DOI: 10.1038/s41591-021-01418-2] [Citation(s) in RCA: 129] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Accepted: 05/28/2021] [Indexed: 02/04/2023]
Abstract
The year 2021 marks the centennial of Banting and Best's landmark description of the discovery of insulin. This discovery and insulin's rapid clinical deployment effectively transformed type 1 diabetes from a fatal diagnosis into a medically manageable chronic condition. In this Review, we describe key accomplishments leading to and building on this momentous occasion in medical history, including advancements in our understanding of the role of insulin in diabetes pathophysiology, the molecular characterization of insulin and the clinical use of insulin. Achievements are also viewed through the lens of patients impacted by insulin therapy and the evolution of insulin pharmacokinetics and delivery over the past 100 years. Finally, we reflect on the future of insulin therapy and diabetes treatment, as well as challenges to be addressed moving forward, so that the full potential of this transformative discovery may be realized.
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Affiliation(s)
- Emily K Sims
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
- The Center for Diabetes & Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA
- The Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Alice L J Carr
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
| | - Richard A Oram
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
- The Academic Kidney Unit, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
| | - Linda A DiMeglio
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
- The Center for Diabetes & Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA
- The Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Carmella Evans-Molina
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
- The Center for Diabetes & Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA.
- The Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
- Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
- Roudebush VA Medical Center, Indianapolis, IN, USA.
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21
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Aktuelle Entwicklungen in der Prävention des Typ-1-Diabetes. DIABETOLOGE 2021. [DOI: 10.1007/s11428-021-00759-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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von Herrath M, Bain SC, Bode B, Clausen JO, Coppieters K, Gaysina L, Gumprecht J, Hansen TK, Mathieu C, Morales C, Mosenzon O, Segel S, Tsoukas G, Pieber TR. Anti-interleukin-21 antibody and liraglutide for the preservation of β-cell function in adults with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Diabetes Endocrinol 2021; 9:212-224. [PMID: 33662334 DOI: 10.1016/s2213-8587(21)00019-x] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 01/12/2021] [Accepted: 01/14/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND Type 1 diabetes is characterised by progressive loss of functional β-cell mass, necessitating insulin treatment. We aimed to investigate the hypothesis that combining anti-interleukin (IL)-21 antibody (for low-grade and transient immunomodulation) with liraglutide (to improve β-cell function) could enable β-cell survival with a reduced risk of complications compared with traditional immunomodulation. METHODS This randomised, parallel-group, placebo-controlled, double-dummy, double-blind, phase 2 trial was done at 94 sites (university hospitals and medical centres) in 17 countries. Eligible participants were adults aged 18-45 years with recently diagnosed type 1 diabetes and residual β-cell function. Individuals with unstable type 1 diabetes (defined by an episode of severe diabetic ketoacidosis within 2 weeks of enrolment) or active or latent chronic infections were excluded. Participants were randomly assigned (1:1:1:1), with stratification by baseline stimulated peak C-peptide concentration (mixed-meal tolerance test [MMTT]), to the combination of anti-IL-21 and liraglutide, anti-IL-21 alone, liraglutide alone, or placebo, all as an adjunct to insulin. Investigators, participants, and funder personnel were masked throughout the treatment period. The primary outcome was the change in MMTT-stimulated C-peptide concentration at week 54 (end of treatment) relative to baseline, measured via the area under the concentration-time curve (AUC) over a 4 h period for the full analysis set (intention-to-treat population consisting of all participants who were randomly assigned). After treatment cessation, participants were followed up for an additional 26-week off-treatment observation period. This trial is registered with ClinicalTrials.gov, NCT02443155. FINDINGS Between Nov 10, 2015, and Feb 27, 2019, 553 adults were assessed for eligibility, of whom 308 were randomly assigned to receive either anti-IL-21 plus liraglutide, anti-IL-21, liraglutide, or placebo (77 assigned to each group). Compared with placebo (ratio to baseline 0·61, 39% decrease), the decrease in MMTT-stimulated C-peptide concentration from baseline to week 54 was significantly smaller with combination treatment (0·90, 10% decrease; estimated treatment ratio 1·48, 95% CI 1·16-1·89; p=0·0017), but not with anti-IL-21 alone (1·23, 0·97-1·57; p=0·093) or liraglutide alone (1·12, 0·87-1·42; p=0·38). Despite greater insulin use in the placebo group, the decrease in HbA1c (a key secondary outcome) at week 54 was greater with all active treatments (-0·50 percentage points) than with placebo (-0·10 percentage points), although the differences versus placebo were not significant. The effects diminished upon treatment cessation. Changes in immune cell subsets across groups were transient and mild (<10% change over time). The most frequently reported adverse events included gastrointestinal disorders, in keeping with the known side-effect profile of liraglutide. The rate of hypoglycaemic events did not differ significantly between active treatment groups and placebo, with an exception of a lower rate in the liraglutide group than in the placebo group during the treatment period. No events of diabetic ketoacidosis were observed. One participant died while on liraglutide (considered unlikely to be related to trial treatment) in connection with three reported adverse events (hypoglycaemic coma, pneumonia, and brain oedema). INTERPRETATION The combination of anti-IL-21 and liraglutide could preserve β-cell function in recently diagnosed type 1 diabetes. The efficacy of this combination appears to be similar to that seen in trials of other disease-modifying interventions in type 1 diabetes, but with a seemingly better safety profile. Efficacy and safety should be further evaluated in a phase 3 trial programme. FUNDING Novo Nordisk.
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Affiliation(s)
| | | | - Bruce Bode
- Atlanta Diabetes Associates, Atlanta, GA, USA; Emory University School of Medicine, Atlanta, GA, USA
| | | | | | | | | | | | - Chantal Mathieu
- Clinical and Experimental Endocrinology, UZ Gasthuisberg, University of Leuven, Leuven, Belgium
| | - Cristobal Morales
- Endocrinology and Nutrition Department, Virgen Macarena Hospital, Seville, Spain
| | - Ofri Mosenzon
- Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Centre, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | | | - George Tsoukas
- Department of Medicine, McGill University, Montreal, QC, Canada
| | - Thomas R Pieber
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
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Liu J, Ting JP, Al-Azzam S, Ding Y, Afshar S. Therapeutic Advances in Diabetes, Autoimmune, and Neurological Diseases. Int J Mol Sci 2021; 22:ijms22062805. [PMID: 33802091 PMCID: PMC8001105 DOI: 10.3390/ijms22062805] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/02/2021] [Accepted: 03/06/2021] [Indexed: 02/08/2023] Open
Abstract
Since 2015, 170 small molecules, 60 antibody-based entities, 12 peptides, and 15 gene- or cell-therapies have been approved by FDA for diverse disease indications. Recent advancement in medicine is facilitated by identification of new targets and mechanisms of actions, advancement in discovery and development platforms, and the emergence of novel technologies. Early disease detection, precision intervention, and personalized treatments have revolutionized patient care in the last decade. In this review, we provide a comprehensive overview of current and emerging therapeutic modalities developed in the recent years. We focus on nine diseases in three major therapeutics areas, diabetes, autoimmune, and neurological disorders. The pathogenesis of each disease at physiological and molecular levels is discussed and recently approved drugs as well as drugs in the clinic are presented.
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Affiliation(s)
- Jinsha Liu
- Protein Engineering, Lilly Biotechnology Center, Eli Lilly and Company, San Diego, CA 92121, USA; (J.L.); (J.P.T.); (Y.D.)
| | - Joey Paolo Ting
- Protein Engineering, Lilly Biotechnology Center, Eli Lilly and Company, San Diego, CA 92121, USA; (J.L.); (J.P.T.); (Y.D.)
| | - Shams Al-Azzam
- Professional Scientific Services, Eurofins Lancaster Laboratories, Lancaster, PA 17605, USA;
| | - Yun Ding
- Protein Engineering, Lilly Biotechnology Center, Eli Lilly and Company, San Diego, CA 92121, USA; (J.L.); (J.P.T.); (Y.D.)
| | - Sepideh Afshar
- Protein Engineering, Lilly Biotechnology Center, Eli Lilly and Company, San Diego, CA 92121, USA; (J.L.); (J.P.T.); (Y.D.)
- Correspondence:
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Antigen-specific immunotherapy combined with a regenerative drug in the treatment of experimental type 1 diabetes. Sci Rep 2020; 10:18927. [PMID: 33144616 PMCID: PMC7609712 DOI: 10.1038/s41598-020-76041-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 10/20/2020] [Indexed: 12/19/2022] Open
Abstract
Type 1 diabetes is an autoimmune disease caused by the destruction of the insulin-producing β-cells. To revert type 1 diabetes, the suppression of the autoimmune attack should be combined with a β-cell replacement strategy. It has been previously demonstrated that liraglutide, a glucagon-like peptide-1 receptor agonist, restores β-cell mass in type 1 diabetes, via α-cell transdifferentiation and neogenesis. We report here that treatment with liraglutide does not prevent type 1 diabetes in the spontaneous non-obese diabetic (NOD) mouse model, but it tends to reduce leukocytic islet infiltration. However, in combination with an immunotherapy based on tolerogenic liposomes, it is effective in ameliorating hyperglycaemia in diabetic NOD mice. Importantly, liraglutide is not detrimental for the tolerogenic effect that liposomes exert on dendritic cells from patients with type 1 diabetes in terms of membrane expression of molecules involved in antigen presentation, immunoregulation and activation. Moreover, the in vivo effect of the combined therapy was tested in mice humanised with peripheral blood mononuclear cells from patients with type 1 diabetes, showing no adverse effects in leukocyte subsets. In conclusion, the combination therapy with liraglutide and a liposome-based immunotherapy is a promising candidate strategy for type 1 diabetes.
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Rosenzwajg M, Salet R, Lorenzon R, Tchitchek N, Roux A, Bernard C, Carel JC, Storey C, Polak M, Beltrand J, Amouyal C, Hartemann A, Corbeau P, Vicaut E, Bibal C, Bougnères P, Tran TA, Klatzmann D. Low-dose IL-2 in children with recently diagnosed type 1 diabetes: a Phase I/II randomised, double-blind, placebo-controlled, dose-finding study. Diabetologia 2020; 63:1808-1821. [PMID: 32607749 DOI: 10.1007/s00125-020-05200-w] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 05/06/2020] [Indexed: 12/21/2022]
Abstract
AIMS/HYPOTHESIS Low-dose IL-2 (ld-IL2) selectively activates and expands regulatory T cells (Tregs) and thus has the potential to skew the regulatory/effector T (Treg/Teff) cell balance towards improved regulation. We investigated which low doses of IL-2 would more effectively and safely activate Tregs during a 1 year treatment in children with recently diagnosed type 1 diabetes. METHODS Dose Finding Study of IL-2 at Ultra-low Dose in Children With Recently Diagnosed Type 1 Diabetes (DF-IL2-Child) was a multicentre, double-blinded, placebo-controlled, dose-finding Phase I/II clinical trial conducted in four centres at university hospitals in France: 24 children (7-14 years old) with type 1 diabetes diagnosed within the previous 3 months were randomly assigned 1:1:1:1 to treatment by a centralised randomisation system, leading to a 7/5/6/6 patient distribution of placebo or IL-2 at doses of 0.125, 0.250 or 0.500 million international units (MIU)/m2, given daily for a 5 day course and then fortnightly for 1 year. A study number was attributed to patients by an investigator unaware of the randomisation list and all participants as well as investigators and staff involved in the study conduct and analyses were blinded to treatments. The primary outcome was change in Tregs, expressed as a percentage of CD4+ T cells at day 5. It pre-specified that a ≥60% increase in Tregs from baseline would identify Treg high responders. RESULTS There were no serious adverse events. Non-serious adverse events (NSAEs) were transient and mild to moderate. In treated patients vs placebo, the commonest NSAE was injection site reaction (37.9% vs 3.4%), whereas other NSAEs were at the same level (23.3% vs 19.2%). ld-IL2 induced a dose-dependent increase in the mean proportion of Tregs, from 23.9% (95% CI -11.8, 59.6) at the lowest to 77.2% (44.7, 109.8) at the highest dose, which was significantly different from placebo for all dose groups. However, the individual Treg responses to IL-2 were variable and fluctuated over time. Seven patients, all among those treated with the 0.250 and 0.500 MIU m-2 day-1 doses, were Treg high responders. At baseline, they had lower Treg proportions in CD4+ cells than Treg low responders, and serum soluble IL-2 receptor α (sIL-2RA) and vascular endothelial growth factor receptor 2 (VEGFR2) levels predicted the Treg response after the 5 day course. There was no significant change in glycaemic control in any of the dose groups compared with placebo. However, there was an improved maintenance of induced C-peptide production at 1 year in the seven Treg high responders as compared with low responders. CONCLUSIONS/INTERPRETATION The safety profile at all doses, the dose-dependent effects on Tregs and the observed variability of the Treg response to ld-IL2 in children with newly diagnosed type 1 diabetes call for use of the highest dose in future developments. The better preservation of insulin production in Treg high responders supports the potential of Tregs in regulating autoimmunity in type 1 diabetes, and warrants pursuing the investigation of ld-IL2 for its treatment and prevention. TRIAL REGISTRATION ClinicalTrials.gov NCT01862120. FUNDING Assistance Publique-Hôpitaux de Paris, Investissements d'Avenir programme (ANR-11-IDEX-0004-02, LabEx Transimmunom and ANR-16-RHUS-0001, RHU iMAP) and European Research Council Advanced Grant (FP7-IDEAS-ERC-322856, TRiPoD).
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Affiliation(s)
- Michelle Rosenzwajg
- Clinical Investigation Center for Biotherapies and Inflammation-Immunopathology-Biotherapy Department (i2B), AP-HP.Sorbonne Université, Pitié-Salpêtrière Hospital, 83 Bd de l'Hôpital, F-75013, Paris, France
- UMR_S 959, Immunology-Immunopathology-Immunotherapy (i3), Sorbonne Université and Inserm, Paris, France
| | - Randa Salet
- Department of Paediatrics, Nîmes University Hospital and Inserm U1183, Montpellier University, Montpellier, France
| | - Roberta Lorenzon
- Clinical Investigation Center for Biotherapies and Inflammation-Immunopathology-Biotherapy Department (i2B), AP-HP.Sorbonne Université, Pitié-Salpêtrière Hospital, 83 Bd de l'Hôpital, F-75013, Paris, France
- UMR_S 959, Immunology-Immunopathology-Immunotherapy (i3), Sorbonne Université and Inserm, Paris, France
| | - Nicolas Tchitchek
- Clinical Investigation Center for Biotherapies and Inflammation-Immunopathology-Biotherapy Department (i2B), AP-HP.Sorbonne Université, Pitié-Salpêtrière Hospital, 83 Bd de l'Hôpital, F-75013, Paris, France
- UMR_S 959, Immunology-Immunopathology-Immunotherapy (i3), Sorbonne Université and Inserm, Paris, France
| | - Alexandra Roux
- Clinical Investigation Center for Biotherapies and Inflammation-Immunopathology-Biotherapy Department (i2B), AP-HP.Sorbonne Université, Pitié-Salpêtrière Hospital, 83 Bd de l'Hôpital, F-75013, Paris, France
- UMR_S 959, Immunology-Immunopathology-Immunotherapy (i3), Sorbonne Université and Inserm, Paris, France
| | - Claude Bernard
- Clinical Investigation Center for Biotherapies and Inflammation-Immunopathology-Biotherapy Department (i2B), AP-HP.Sorbonne Université, Pitié-Salpêtrière Hospital, 83 Bd de l'Hôpital, F-75013, Paris, France
- UMR_S 959, Immunology-Immunopathology-Immunotherapy (i3), Sorbonne Université and Inserm, Paris, France
| | - Jean-Claude Carel
- Department of Paediatric Endocrinology and Diabetology, and Centre de Référence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité, Robert-Debré Hospital, AP-HP Nord-Université de Paris Diderot & UFR de Médecine Paris Diderot, Paris, France
| | - Caroline Storey
- Department of Paediatric Endocrinology and Diabetology, and Centre de Référence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité, Robert-Debré Hospital, AP-HP Nord-Université de Paris Diderot & UFR de Médecine Paris Diderot, Paris, France
| | - Michel Polak
- Department of Paediatric Endocrinology, Gynecology and Diabetology, and Centre de Référence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité, Necker Enfants Malades Hospital, AP-HP.Centre & Université de Paris, UFR de Médecine Paris Descartes, Paris, France
| | - Jacques Beltrand
- Department of Paediatric Endocrinology, Gynecology and Diabetology, and Centre de Référence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité, Necker Enfants Malades Hospital, AP-HP.Centre & Université de Paris, UFR de Médecine Paris Descartes, Paris, France
| | - Chloé Amouyal
- Department of Diabetology, Pitié-Salpêtrière Hospital, AP-HP. Sorbonne Université, Paris, France
| | - Agnès Hartemann
- Department of Diabetology, Pitié-Salpêtrière Hospital, AP-HP. Sorbonne Université, Paris, France
| | - Pierre Corbeau
- Immunology Department, Nîmes University Hospital, Nîmes, France
| | - Eric Vicaut
- Lariboisière Hospital, Clinical Trial Unit, AP-HP.Nord, Paris, France
| | - Cecile Bibal
- Department of Paediatric Endocrinology, Bicêtre Hospital, AP-HP.Université Paris Saclay, Le Kremlin-Bicêtre, France
| | - Pierre Bougnères
- Department of Paediatric Endocrinology, Bicêtre Hospital, AP-HP.Université Paris Saclay, Le Kremlin-Bicêtre, France
| | - Tu-Anh Tran
- Department of Paediatrics, Nîmes University Hospital and Inserm U1183, Montpellier University, Montpellier, France
| | - David Klatzmann
- Clinical Investigation Center for Biotherapies and Inflammation-Immunopathology-Biotherapy Department (i2B), AP-HP.Sorbonne Université, Pitié-Salpêtrière Hospital, 83 Bd de l'Hôpital, F-75013, Paris, France.
- UMR_S 959, Immunology-Immunopathology-Immunotherapy (i3), Sorbonne Université and Inserm, Paris, France.
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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.
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Warshauer JT, Bluestone JA, Anderson MS. New Frontiers in the Treatment of Type 1 Diabetes. Cell Metab 2020; 31:46-61. [PMID: 31839487 PMCID: PMC6986815 DOI: 10.1016/j.cmet.2019.11.017] [Citation(s) in RCA: 156] [Impact Index Per Article: 31.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 11/08/2019] [Accepted: 11/18/2019] [Indexed: 12/30/2022]
Abstract
Type 1 diabetes is an autoimmune disease caused by the immune-mediated destruction of pancreatic β cells that results in lifelong absolute insulin deficiency. For nearly a century, insulin replacement has been the only therapy for most people living with this disease. Recent advances in technology and our understanding of β cell development, glucose metabolism, and the underlying immune pathogenesis of the disease have led to innovative therapeutic and preventative approaches. A paradigm shift in immunotherapy development toward the targeting of islet-specific immune pathways involved in tolerance has driven the development of therapies that may allow for the prevention or reversal of this disease while avoiding toxicities associated with historical approaches that were broadly immunosuppressive. In this review, we discuss successes, failures, and emerging pharmacological therapies for type 1 diabetes that are changing how we approach this disease, from improving glycemic control to developing the "holy grail" of disease prevention.
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Affiliation(s)
- Jeremy T Warshauer
- Endocrine Division, Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA; Diabetes Center, University of California San Francisco, San Francisco, CA 94143, USA
| | - Jeffrey A Bluestone
- Diabetes Center, University of California San Francisco, San Francisco, CA 94143, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA
| | - Mark S Anderson
- Endocrine Division, Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA; Diabetes Center, University of California San Francisco, San Francisco, CA 94143, USA.
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Sneddon JB, Tang Q, Stock P, Bluestone JA, Roy S, Desai T, Hebrok M. Stem Cell Therapies for Treating Diabetes: Progress and Remaining Challenges. Cell Stem Cell 2019; 22:810-823. [PMID: 29859172 DOI: 10.1016/j.stem.2018.05.016] [Citation(s) in RCA: 174] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Restoration of insulin independence and normoglycemia has been the overarching goal in diabetes research and therapy. While whole-organ and islet transplantation have become gold-standard procedures in achieving glucose control in diabetic patients, the profound lack of suitable donor tissues severely hampers the broad application of these therapies. Here, we describe current efforts aimed at generating a sustainable source of functional human stem cell-derived insulin-producing islet cells for cell transplantation and present state-of-the-art efforts to protect such cells via immune modulation and encapsulation strategies.
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Affiliation(s)
- Julie B Sneddon
- Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA; Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Qizhi Tang
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Peter Stock
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Jeffrey A Bluestone
- Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Parker Institute for Cancer Immunotherapy, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Shuvo Roy
- UCSF-UC Berkeley Joint Ph.D. Program in Bioengineering, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Tejal Desai
- UCSF-UC Berkeley Joint Ph.D. Program in Bioengineering, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Matthias Hebrok
- Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
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Funda DP, Palová-Jelínková L, Goliáš J, Kroulíková Z, Fajstová A, Hudcovic T, Špíšek R. Optimal Tolerogenic Dendritic Cells in Type 1 Diabetes (T1D) Therapy: What Can We Learn From Non-obese Diabetic (NOD) Mouse Models? Front Immunol 2019; 10:967. [PMID: 31139178 PMCID: PMC6527741 DOI: 10.3389/fimmu.2019.00967] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 04/15/2019] [Indexed: 12/21/2022] Open
Abstract
Tolerogenic dendritic cells (tolDCs) are explored as a promising standalone or combination therapy in type 1 diabetes (T1D). The therapeutic application of tolDCs, including in human trials, has been tested also in other autoimmune diseases, however, T1D displays some unique features. In addition, unlike in several disease-induced animal models of autoimmune diseases, the prevalent animal model for T1D, the NOD mouse, develops diabetes spontaneously. This review compares evidence of various tolDCs approaches obtained from animal (mainly NOD) models of T1D with a focus on parameters of this cell-based therapy such as protocols of tolDC preparation, antigen-specific vs. unspecific approaches, doses of tolDCs and/or autoantigens, application schemes, application routes, the migration of tolDCs as well as their preventive, early pre-onset intervention or curative effects. This review also discusses perspectives of tolDC therapy and areas of preclinical research that are in need of better clarification in animal models in a quest for effective and optimal tolDC therapies of T1D in humans.
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Affiliation(s)
- David P Funda
- Institute of Microbiology of the Czech Academy of Sciences, v.v.i., Prague, Czechia
| | - Lenka Palová-Jelínková
- SOTIO a s., Prague, Czechia.,Department of Immunology, 2nd Medical School, Charles University, Prague, Czechia
| | - Jaroslav Goliáš
- Institute of Microbiology of the Czech Academy of Sciences, v.v.i., Prague, Czechia
| | - Zuzana Kroulíková
- Institute of Microbiology of the Czech Academy of Sciences, v.v.i., Prague, Czechia
| | - Alena Fajstová
- Institute of Microbiology of the Czech Academy of Sciences, v.v.i., Prague, Czechia
| | - Tomáš Hudcovic
- Institute of Microbiology of the Czech Academy of Sciences, v.v.i., Prague, Czechia
| | - Radek Špíšek
- SOTIO a s., Prague, Czechia.,Department of Immunology, 2nd Medical School, Charles University, Prague, Czechia
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Karras SN, Koufakis T, Zebekakis P, Kotsa K. Pharmacologic adjunctive to insulin therapies in type 1 diabetes: The journey has just begun. World J Diabetes 2019; 10:234-240. [PMID: 31040899 PMCID: PMC6475707 DOI: 10.4239/wjd.v10.i4.234] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 03/13/2019] [Accepted: 03/28/2019] [Indexed: 02/05/2023] Open
Abstract
Treatment of type 1 diabetes (T1D) is currently based exclusively on insulin replacement therapy. However, there is a need for better glycemic control, lower hypoglycemia rates, more effective weight management, and further reduction of cardiovascular risk in people with T1D. In this context, agents from the pharmaceutical quiver of type 2 diabetes are being tested in clinical trials, as adjunctive to insulin therapies for T1D patients. Despite the limited amount of relevant evidence and the inter-class variability, it can be said that these agents have a role in optimizing metabolic control, assisting weight management and reducing glycemic variability in people with T1D. Specific safety issues, including the increased risk of hypoglycemia and diabetic ketoacidosis, as well as the effects of these treatments on major cardiovascular outcomes should be further assessed by future studies, before these therapeutic choices become widely available for T1D management.
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Affiliation(s)
- Spyridon N Karras
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki 55535, Greece
| | - Theocharis Koufakis
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki 55535, Greece
| | - Pantelis Zebekakis
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki 55535, Greece
| | - Kalliopi Kotsa
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki 55535, Greece
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Abstract
Type 1 diabetes is a chronic autoimmune disease characterised by insulin deficiency and resultant hyperglycaemia. Knowledge of type 1 diabetes has rapidly increased over the past 25 years, resulting in a broad understanding about many aspects of the disease, including its genetics, epidemiology, immune and β-cell phenotypes, and disease burden. Interventions to preserve β cells have been tested, and several methods to improve clinical disease management have been assessed. However, wide gaps still exist in our understanding of type 1 diabetes and our ability to standardise clinical care and decrease disease-associated complications and burden. This Seminar gives an overview of the current understanding of the disease and potential future directions for research and care.
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Affiliation(s)
- Linda A DiMeglio
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
| | - Carmella Evans-Molina
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Richard A Oram
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, and The Academic Kidney Unit, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
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Bingley PJ, Wherrett DK, Shultz A, Rafkin LE, Atkinson MA, Greenbaum CJ. Type 1 Diabetes TrialNet: A Multifaceted Approach to Bringing Disease-Modifying Therapy to Clinical Use in Type 1 Diabetes. Diabetes Care 2018; 41:653-661. [PMID: 29559451 PMCID: PMC5860837 DOI: 10.2337/dc17-0806] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Accepted: 12/13/2017] [Indexed: 02/03/2023]
Abstract
What will it take to bring disease-modifying therapy to clinical use in type 1 diabetes? Coordinated efforts of investigators involved in discovery, translational, and clinical research operating in partnership with funders and industry and in sync with regulatory agencies are needed. This Perspective describes one such effort, Type 1 Diabetes TrialNet, a National Institutes of Health-funded and JDRF-supported international clinical trials network that emerged from the Diabetes Prevention Trial-Type 1 (DPT-1). Through longitudinal natural history studies, as well as trials before and after clinical onset of disease combined with mechanistic and ancillary investigations to enhance scientific understanding and translation to clinical use, TrialNet is working to bring disease-modifying therapies to individuals with type 1 diabetes. Moreover, TrialNet uses its expertise and experience in clinical studies to increase efficiencies in the conduct of trials and to reduce the burden of participation on individuals and families. Herein, we highlight key contributions made by TrialNet toward a revised understanding of the natural history of disease and approaches to alter disease course and outline the consortium's plans for the future.
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Affiliation(s)
- Polly J Bingley
- Diabetes and Metabolism, Bristol Medical School, University of Bristol, Bristol, U.K
| | - Diane K Wherrett
- Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada
| | - Ann Shultz
- Diabetes Research Program, Benaroya Research Institute, Seattle, WA
| | - Lisa E Rafkin
- University of Miami Diabetes Research Institute, Miami, FL
| | - Mark A Atkinson
- Departments of Pathology and Pediatrics, University of Florida College of Medicine,Gainesville, FL
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Fakir M, Penfornis A, Elian N, Cugnenc PH, Altman J. Grafted Immunoisolated Human Benign Insulinoma Reduces the Incidence of Diabetes in Young NOD Mice without Abolishing the Auto-Immunity. Int J Artif Organs 2018. [DOI: 10.1177/039139889702001107] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Exogenous insulin may prevent the auto-immunity of diabetes in rodents. We studied the preventive effect of a safe endogenous insulin delivery in the diabetes-prone NOD mouse by immuno-protected human insulinoma grafts. Perm-selective macrocapsules seeded with human insulinoma were implanted in 34 young NOD mice, 4 and 8 weeks old. The animals were observed 18 months and compared to 34 NOD mice grafted with empty fibers and 25 simply observed. Before grafting, the capacity of the macrocapsules to release insulin was assessed in vitro by perifusion studies and by implantation to 12 diabetic NOD mice. At perifusion, the insulin release of the macrocapsules responded to step changes in glucose. During the in vivo study, the capsules reduced the glycemia of diabetic mice from 18±3.5 to 7.3±2.1 mmol/L. In the study groups, the survival rate without diabetes (50-70%) was statistically different from controls (10-20%). Recipient's splenocytes transplanted to irradiated male NOD mice transferred the autoimmunity in 75-83% of grafted mice and 86-100% of controls. Insulitis was persistent in all, although milder in the grafted mice. Encapsulated insulinoma prevents diabetes in the NOD mouse without abolishing the auto-immunity. The quantity and quality of the tissues needed and the best moment to graft them have to be determined. The prevention of diabetes by encapsulated pancreatic tissue is appealing because of its simplicity and safety.
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Affiliation(s)
- M. Fakir
- Service de Nephrologie, Hôpital Manchester, Charleville-Mézières
- Service de Diabétologie-Nutrition-Transplantation, Laennec Hospital, Paris
| | | | - N. Elian
- Service de Chirurgie, Laennec Hospital, Paris - France
| | - P.-H. Cugnenc
- Service de Chirurgie, Laennec Hospital, Paris - France
| | - J.J. Altman
- Service de Diabétologie-Nutrition-Transplantation, Laennec Hospital, Paris
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Abstract
PURPOSE OF REVIEW The genetic susceptibility and dominant protection for type 1 diabetes (T1D) associated with human leukocyte antigen (HLA) haplotypes, along with minor risk variants, have long been thought to shape the T cell receptor (TCR) repertoire and eventual phenotype of autoreactive T cells that mediate β-cell destruction. While autoantibodies provide robust markers of disease progression, early studies tracking autoreactive T cells largely failed to achieve clinical utility. RECENT FINDINGS Advances in acquisition of pancreata and islets from T1D organ donors have facilitated studies of T cells isolated from the target tissues. Immunosequencing of TCR α/β-chain complementarity determining regions, along with transcriptional profiling, offers the potential to transform biomarker discovery. Herein, we review recent studies characterizing the autoreactive TCR signature in T1D, emerging technologies, and the challenges and opportunities associated with tracking TCR molecular profiles during the natural history of T1D.
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Affiliation(s)
- Laura M Jacobsen
- Department of Pediatrics, College of Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA
| | - Amanda Posgai
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA
| | - Howard R Seay
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA
| | - Michael J Haller
- Department of Pediatrics, College of Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA
| | - Todd M Brusko
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA.
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Abstract
PURPOSE OF REVIEW Type 1 diabetes (T1D) is an autoimmune disease marked by β-cell destruction. Immunotherapies for T1D have been investigated since the 1980s and have focused on restoration of tolerance, T cell or B cell inhibition, regulatory T cell (Treg) induction, suppression of innate immunity and inflammation, immune system reset, and islet transplantation. The purpose of this review is to provide an overview and lessons learned from single immunotherapy trials, describe recent and ongoing combination immunotherapy trials, and provide perspectives on strategies for future combination clinical interventions aimed at preserving insulin secretion in T1D. RECENT FINDINGS Combination immunotherapies have had mixed results in improving short-term glycemic control and insulin secretion in recent-onset T1D. A handful of studies have successfully reached their primary end-point of improved insulin secretion in recent-onset T1D. However, long-term improvements glycemic control and the restoration of insulin independence remain elusive. Future interventions should focus on strategies that combine immunomodulation with efforts to alleviate β-cell stress and address the formation of antigens that activate autoimmunity.
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Affiliation(s)
- Robert N Bone
- Department of Medicine, Indiana School of Medicine, 635 Barnhill Dr, MS 2031A, Indianapolis, IN, 46202, USA
- Center for Diabetes & Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Carmella Evans-Molina
- Department of Medicine, Indiana School of Medicine, 635 Barnhill Dr, MS 2031A, Indianapolis, IN, 46202, USA.
- Center for Diabetes & Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
- Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
- Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
- Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
- Roudebush VA Medical Center, Indianapolis, IN, 46202, USA.
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Hao W, Gitelman S, DiMeglio LA, Boulware D, Greenbaum CJ. Fall in C-Peptide During First 4 Years From Diagnosis of Type 1 Diabetes: Variable Relation to Age, HbA1c, and Insulin Dose. Diabetes Care 2016; 39:1664-70. [PMID: 27422577 PMCID: PMC5033079 DOI: 10.2337/dc16-0360] [Citation(s) in RCA: 112] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 06/24/2016] [Indexed: 02/03/2023]
Abstract
OBJECTIVE We aimed to describe the natural history of residual insulin secretion in Type 1 Diabetes TrialNet participants over 4 years from diagnosis and relate this to previously reported alternative clinical measures reflecting β-cell secretory function. RESEARCH DESIGN AND METHODS Data from 407 subjects from 5 TrialNet intervention studies were analyzed. All subjects had baseline stimulated C-peptide values of ≥0.2 nmol/L from mixed-meal tolerance tests (MMTTs). During semiannual visits, C-peptide values from MMTTs, HbA1c, and insulin doses were obtained. RESULTS The percentage of individuals with stimulated C-peptide of ≥0.2 nmol/L or detectable C-peptide of ≥0.017 nmol/L continued to diminish over 4 years; this was markedly influenced by age. At 4 years, only 5% maintained their baseline C-peptide secretion. The expected inverse relationships between C-peptide and HbA1c or insulin doses varied over time and with age. Combined clinical variables, such as insulin-dose adjusted HbA1c (IDAA1C) and the relationship of IDAA1C to C-peptide, also were influenced by age and time from diagnosis. Models using these clinical measures did not fully predict C-peptide responses. IDAA1C ≤9 underestimated the number of individuals with stimulated C-peptide ≥0.2 nmol/L, especially in children. CONCLUSIONS Current trials of disease-modifying therapy for type 1 diabetes should continue to use C-peptide as a primary end point of β-cell secretory function. Longer duration of follow-up is likely to provide stronger evidence of the effect of disease-modifying therapy on preservation of β-cell function.
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Affiliation(s)
- Wei Hao
- Diabetes Clinical Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA
| | - Steven Gitelman
- Department of Pediatrics, University of California, San Francisco, San Francisco, CA
| | | | - David Boulware
- Department of Pediatrics, University of South Florida, Tampa, FL
| | - Carla J Greenbaum
- Diabetes Clinical Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA
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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.
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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.
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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.
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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
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39
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Gitelman SE, Bluestone JA. Regulatory T cell therapy for type 1 diabetes: May the force be with you. J Autoimmun 2016; 71:78-87. [DOI: 10.1016/j.jaut.2016.03.011] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Accepted: 03/18/2016] [Indexed: 12/14/2022]
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40
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Gitelman SE, Gottlieb PA, Felner EI, Willi SM, Fisher LK, Moran A, Gottschalk M, Moore WV, Pinckney A, Keyes-Elstein L, Harris KM, Kanaparthi S, Phippard D, Ding L, Bluestone JA, Ehlers MR. Antithymocyte globulin therapy for patients with recent-onset type 1 diabetes: 2 year results of a randomised trial. Diabetologia 2016; 59:1153-61. [PMID: 27053235 PMCID: PMC4869699 DOI: 10.1007/s00125-016-3917-4] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2015] [Accepted: 02/17/2016] [Indexed: 01/13/2023]
Abstract
AIMS/HYPOTHESIS Type 1 diabetes results from T cell mediated destruction of beta cells. We conducted a trial of antithymocyte globulin (ATG) in new-onset type 1 diabetes (the Study of Thymoglobulin to ARrest T1D [START] trial). Our goal was to evaluate the longer-term safety and efficacy of ATG in preserving islet function at 2 years. METHODS A multicentre, randomised, double-blind, placebo-controlled trial of 6.5 mg/kg ATG (Thymoglobulin) vs placebo in patients with new-onset type 1 diabetes was conducted at seven university medical centres and one Children's Hospital in the USA. The site-stratified randomisation scheme was computer generated at the data coordinating centre using permuted-blocks of size 3 or 6. Eligible participants were between the ages of 12 and 35, and enrolled within 100 days from diagnosis. Subjects were randomised to 6.5 mg/kg ATG (thymoglobulin) vs placebo in a 2:1 ratio. Participants were blinded, and the study design included two sequential patient-care teams: an unblinded study-drug administration team (for the first 8 weeks), and a blinded diabetes management team (for the remainder of the study). Endpoints assessed at 24 months included meal-stimulated C-peptide AUC, safety and immunological responses. RESULTS Fifty-eight patients were enrolled; at 2 years, 35 assigned to ATG and 16 to placebo completed the study. The pre-specified endpoints were not met. In post hoc analyses, older patients (age 22-35 years) in the ATG group had significantly greater C-peptide AUCs at 24 months than placebo patients. Using complete preservation of baseline C-peptide at 24 months as threshold, nine of 35 ATG-treated participants (vs 2/16 placebo participants) were classified as responders; nine of 11 responders (67%) were older. All participants reported at least one adverse event (AE), with 1,148 events in the 38 ATG participants vs 415 in the 20 placebo participants; a comparable number of infections were noted in the ATG and placebo groups, with no opportunistic infections nor difficulty clearing infections in either group. Circulating T cell subsets depleted by ATG partially reconstituted, but regulatory, naive and central memory subsets remained significantly depleted at 24 months. Beta cell autoantibodies did not change over the 24 months in the ATG-treated or placebo participants. At 12 months, ATG-treated participants had similar humoral immune responses to tetanus and HepA vaccines as placebo-treated participants, and no increased infections. CONCLUSIONS/INTERPRETATION A brief course of ATG substantially depleted T cell subsets, including regulatory cells, but did not preserve islet function 24 months later in the majority of patients with new-onset type 1 diabetes. ATG preserved C-peptide secretion in older participants, which may warrant further study. TRIAL REGISTRATION ClinicalTrials.gov NCT00515099 PUBLIC DATA REPOSITORY: START datasets are available in TrialShare www.itntrialshare.org FUNDING National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH). The trial was conducted by the Immune Tolerance Network (ITN).
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Affiliation(s)
- Stephen E Gitelman
- Division of Pediatric Endocrinology, University of California San Francisco, Mission Hall, 550 16th Street, 4th Floor, Box 0434, San Francisco, CA, 94158-2549, USA.
- Diabetes Center, University of California San Francisco, San Francisco, CA, USA.
| | | | - Eric I Felner
- Division of Pediatric Endocrinology, Emory University School of Medicine, Atlanta, GA, USA
| | - Steven M Willi
- Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Lynda K Fisher
- Department of Endocrinology and Metabolism, Children's Hospital of Los Angeles, Los Angeles, CA, USA
| | - Antoinette Moran
- Department of Pediatrics, Division of Pediatrics Endocrinology, University of Minnesota, Minneapolis, MN, USA
| | - Michael Gottschalk
- Department of Pediatrics, University of California San Diego, San Diego, CA, USA
| | - Wayne V Moore
- Department of Pediatrics, Division of Pediatric Endocrinology, Children's Mercy Hospital and University of Missouri-Kansas City, Kansas City, MO, USA
| | | | | | | | | | - Deborah Phippard
- Immune Tolerance Network, Bethesda, MD, USA
- Precision for Medicine, Bethesda, MD, USA
| | - Linna Ding
- National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA
| | - Jeffrey A Bluestone
- Diabetes Center, University of California San Francisco, San Francisco, CA, USA
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McLaughlin KA, Richardson CC, Ravishankar A, Brigatti C, Liberati D, Lampasona V, Piemonti L, Morgan D, Feltbower RG, Christie MR. Identification of Tetraspanin-7 as a Target of Autoantibodies in Type 1 Diabetes. Diabetes 2016; 65:1690-8. [PMID: 26953162 DOI: 10.2337/db15-1058] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Accepted: 03/01/2016] [Indexed: 01/25/2023]
Abstract
The presence of autoantibodies to multiple-islet autoantigens confers high risk for the development of type 1 diabetes. Four major autoantigens are established (insulin, glutamate decarboxylase, IA2, and zinc transporter-8), but the molecular identity of a fifth, a 38-kDa membrane glycoprotein (Glima), is unknown. Glima antibodies have been detectable only by immunoprecipitation from extracts of radiolabeled islet or neuronal cells. We sought to identify Glima to enable efficient assay of these autoantibodies. Mouse brain and lung were shown to express Glima. Membrane glycoproteins from extracts of these organs were enriched by detergent phase separation, lectin affinity chromatography, and SDS-PAGE. Proteins were also immunoaffinity purified from brain extracts using autoantibodies from the sera of patients with diabetes before SDS-PAGE. Eluates from gel regions equivalent to 38 kDa were analyzed by liquid chromatography-tandem mass spectrometry for protein identification. Three proteins were detected in samples from the brain and lung extracts, and in the immunoaffinity-purified sample, but not in the negative control. Only tetraspanin-7, a multipass transmembrane glycoprotein with neuroendocrine expression, had physical characteristics expected of Glima. Tetraspanin-7 was confirmed as an autoantigen by demonstrating binding to autoantibodies in type 1 diabetes. We identify tetraspanin-7 as a target of autoimmunity in diabetes, allowing its exploitation for diabetes prediction and immunotherapy.
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Affiliation(s)
- Kerry A McLaughlin
- Diabetes Research Group, Division of Diabetes & Nutritional Sciences, King's College London, London, U.K
| | - Carolyn C Richardson
- Diabetes Research Group, Division of Diabetes & Nutritional Sciences, King's College London, London, U.K. School of Life Sciences, University of Lincoln, Lincoln, U.K
| | - Aarthi Ravishankar
- Diabetes Research Group, Division of Diabetes & Nutritional Sciences, King's College London, London, U.K
| | - Cristina Brigatti
- Diabetes Research Institute, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute, Milan, Italy
| | - Daniela Liberati
- Division of Genetics and Cellular Biology, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute, Milan, Italy
| | - Vito Lampasona
- Division of Genetics and Cellular Biology, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute, Milan, Italy
| | - Lorenzo Piemonti
- Diabetes Research Institute, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute, Milan, Italy
| | - Diana Morgan
- Division of Epidemiology & Biostatistics, School of Medicine, University of Leeds, Leeds, U.K
| | - Richard G Feltbower
- Division of Epidemiology & Biostatistics, School of Medicine, University of Leeds, Leeds, U.K
| | - Michael R Christie
- Diabetes Research Group, Division of Diabetes & Nutritional Sciences, King's College London, London, U.K. School of Life Sciences, University of Lincoln, Lincoln, U.K.
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42
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Chatenoud L. World Diabetes Day: Perspectives on immunotherapy of Type 1 Diabetes. Eur J Immunol 2016; 45:2968-70. [PMID: 26645859 DOI: 10.1002/eji.201570114] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Affiliation(s)
- Lucienne Chatenoud
- Université Paris Descartes, Sorbonne Paris Cité, Paris, France.,INSERM U1151, Hôpital Necker-Enfants Malades, Paris, France.,CNRS UMR 8253, Hôpital Necker-Enfants Malades, Paris, France
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43
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Creusot RJ, Battaglia M, Roncarolo MG, Fathman CG. Concise Review: Cell-Based Therapies and Other Non-Traditional Approaches for Type 1 Diabetes. Stem Cells 2016; 34:809-19. [PMID: 26840009 PMCID: PMC5021120 DOI: 10.1002/stem.2290] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Accepted: 12/07/2015] [Indexed: 01/01/2023]
Abstract
The evolution of Type 1 diabetes (T1D) therapy has been marked by consecutive shifts, from insulin replacement to immunosuppressive drugs and targeted biologics (following the understanding that T1D is an autoimmune disease), and to more disease‐specific or patient‐oriented approaches such as antigen‐specific and cell‐based therapies, with a goal to provide efficacy, safety, and long‐term protection. At the same time, another important paradigm shift from treatment of new onset T1D patients to prevention in high‐risk individuals has taken place, based on the hypothesis that therapeutic approaches deemed sufficiently safe may show better efficacy if applied early enough to maintain endogenous β cell function, a concept supported by many preclinical studies. This new strategy has been made possible by capitalizing on a variety of biomarkers that can more reliably estimate the risk and rate of progression of the disease. More advanced (“omic”‐based) biomarkers that also shed light on the underlying contributors of disease for each individual will be helpful to guide the choice of the most appropriate therapies, or combinations thereof. In this review, we present current efforts to stratify patients according to biomarkers and current alternatives to conventional drug‐based therapies for T1D, with a special emphasis on cell‐based therapies, their status in the clinic and potential for treatment and/or prevention. Stem Cells2016;34:809–819
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Affiliation(s)
- Remi J Creusot
- Department of Medicine, Columbia Center for Translational Immunology and Naomi Berrie Diabetes Center, Columbia University Medical Center, New York, USA
| | - Manuela Battaglia
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Maria-Grazia Roncarolo
- Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine Stanford, CA, USA
| | - C Garrison Fathman
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine Stanford, CA, USA
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44
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Virk J, Ritz B, Li J, Obel C, Olsen J. Childhood Bereavement and Type 1 Diabetes: a Danish National Register Study. Paediatr Perinat Epidemiol 2016; 30:86-92. [PMID: 26444317 DOI: 10.1111/ppe.12247] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND Death of a close family member such as a parent or a sibling can cause prolonged stress and changes in the family structure that may have extensive social and health effects on a young child. The aim of this paper is to examine the rate of type 1 diabetes following bereavement due to death of a first-degree family member in early life. METHODS We used data from the Danish Civil Registration System (CRS) to identify singleton births in Denmark born 1 January 1980 through 31 December 2005, n = 1 740 245 and their next of kin. We categorised children as exposed to bereavement if they lost a mother, father or sibling from age 5 years onwards, the remaining children were considered unexposed. Children were followed until first diagnosis of diabetes, death, emigration, or 31 December 2010. We estimated incidence rate ratios (IRRs) from birth using log-linear Poisson regression models with person-years as an offset variable. Exposed children were followed up for an average of 9.1 years [standard deviation (SD) 6.7] and unexposed children were followed up for an average of 12.3 years (SD 7.3). RESULTS In our sample 94 943 children were exposed to bereavement, and 6110 cases of type 1 diabetes were identified. Bereavement was associated with an increased rate of type 1 diabetes when exposure onset began after 11 years of age (adjusted IRR 1.28, 95% confidence interval 1.08, 1.51). CONCLUSION We found some evidence to indicate an increase in the rate of type 1 diabetes among children exposed to bereavement when exposure occurred after 11 years of age.
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Affiliation(s)
- Jasveer Virk
- Department of Epidemiology, University of California, Los Angeles, Los Angeles, CA
| | - Beate Ritz
- Department of Epidemiology, University of California, Los Angeles, Los Angeles, CA
| | - Jiong Li
- Department of Public Health, Aarhus University, Aarhus, Denmark
| | - Carsten Obel
- Department of Public Health, Aarhus University, Aarhus, Denmark
| | - Jørn Olsen
- Department of Public Health, Aarhus University, Aarhus, Denmark
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45
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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.
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Affiliation(s)
- Diane K Wherrett
- Division of Endocrinology, Department of Pediatrics, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.
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46
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Lord S, Greenbaum CJ. Disease modifying therapies in type 1 diabetes: Where have we been, and where are we going? Pharmacol Res 2015; 98:3-8. [PMID: 25771310 PMCID: PMC4469522 DOI: 10.1016/j.phrs.2015.02.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Accepted: 02/08/2015] [Indexed: 01/10/2023]
Abstract
With more than four decades of clinical research and 25 years of clinical trials, much is known about the natural history of T1D before and after clinical diagnosis. We know that autoimmunity occurs early in life, that islet autoimmunity inevitably leads to clinically overt disease, and that some immune therapies can alter the disease course. In the future, we will likely conduct trials to more deeply explore mechanisms of disease and response to therapy, employ combinations of agents including those aimed at supporting beta cells, consider the use of chronic, intermittent therapy, focus studies on preventing progression from islet autoimmunity, and consider the potential benefits of studying children independently from adults. Much of this work will depend upon clinical trial networks such as Diabetes TrialNet. Such networks not only have the expertise to conduct studies but their sharing of data and samples also allows for discovery work by multiple investigators, laying the groundwork for the future. Working with patients, families, funders and industry, such collaborative networks can accelerate the translation of science to clinical practice to improve the lives of those living with T1D.
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Affiliation(s)
- Sandra Lord
- Diabetes Clinical Research Program, Benaroya Research Institute, Seattle, WA, USA.
| | - Carla J Greenbaum
- Diabetes Clinical Research Program, Benaroya Research Institute, Seattle, WA, USA
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47
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Rigby MR, Harris KM, Pinckney A, DiMeglio LA, Rendell MS, Felner EI, Dostou JM, Gitelman SE, Griffin KJ, Tsalikian E, Gottlieb PA, Greenbaum CJ, Sherry NA, Moore WV, Monzavi R, Willi SM, Raskin P, Keyes-Elstein L, Long SA, Kanaparthi S, Lim N, Phippard D, Soppe CL, Fitzgibbon ML, McNamara J, Nepom GT, Ehlers MR. Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients. J Clin Invest 2015; 125:3285-96. [PMID: 26193635 DOI: 10.1172/jci81722] [Citation(s) in RCA: 235] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Accepted: 06/09/2015] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Type 1 diabetes (T1D) results from destruction of pancreatic β cells by autoreactive effector T cells. We hypothesized that the immunomodulatory drug alefacept would result in targeted quantitative and qualitative changes in effector T cells and prolonged preservation of endogenous insulin secretion by the remaining β cells in patients with newly diagnosed T1D. METHODS In a multicenter, randomized, double-blind, placebo-controlled trial, we compared alefacept (two 12-week courses of 15 mg/wk i.m., separated by a 12-week pause) with placebo in patients with recent onset of T1D. Endpoints were assessed at 24 months and included meal-stimulated C-peptide AUC, insulin use, hypoglycemic events, and immunologic responses. RESULTS A total of 49 patients were enrolled. At 24 months, or 15 months after the last dose of alefacept, both the 4-hour and the 2-hour C-peptide AUCs were significantly greater in the treatment group than in the control group (P = 0.002 and 0.015, respectively). Exogenous insulin requirements were lower (P = 0.002) and rates of major hypoglycemic events were about 50% reduced (P < 0.001) in the alefacept group compared with placebo at 24 months. There was no apparent between-group difference in glycemic control or adverse events. Alefacept treatment depleted CD4+ and CD8+ central memory T cells (Tcm) and effector memory T cells (Tem) (P < 0.01), preserved Tregs, increased the ratios of Treg to Tem and Tcm (P < 0.01), and increased the percentage of PD-1+CD4+ Tem and Tcm (P < 0.01). CONCLUSIONS In patients with newly diagnosed T1D, two 12-week courses of alefacept preserved C-peptide secretion, reduced insulin use and hypoglycemic events, and induced favorable immunologic profiles at 24 months, well over 1 year after cessation of therapy. TRIAL REGISTRATION https://clinicaltrials.gov/ NCT00965458. FUNDING NIH and Astellas.
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Abstract
No treatment to halt the progressive loss of insulin-producing beta-cells in type 1 diabetes mellitus has yet been clinically introduced. Strategies tested have at best only transiently preserved beta-cell function and in many cases with obvious side effects of drugs used. Several studies have suggested that mesenchymal stromal cells exert strong immunomodulatory properties with the capability to prevent or halt diabetes development in animal models of type 1 diabetes. A multitude of mechanisms has been forwarded to exert this effect. Recently, we translated this strategy into a first clinical phase I/IIa trial and observed no side effects, and preserved or even increased C-peptide responses to a mixed meal tolerance test during the first year after treatment. Future blinded, larger studies, with extended follow-up, are clearly of interest to investigate this treatment concept.
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Affiliation(s)
- Per-Ola Carlsson
- Department of Medical Cell Biology, Uppsala University, Husargatan 3, Box 571, 75123, Uppsala, Sweden,
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49
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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.
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Affiliation(s)
- Jay S Skyler
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
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50
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Rosenzwajg M, Churlaud G, Mallone R, Six A, Dérian N, Chaara W, Lorenzon R, Long SA, Buckner JH, Afonso G, Pham HP, Hartemann A, Yu A, Pugliese A, Malek TR, Klatzmann D. Low-dose interleukin-2 fosters a dose-dependent regulatory T cell tuned milieu in T1D patients. J Autoimmun 2015; 58:48-58. [PMID: 25634360 DOI: 10.1016/j.jaut.2015.01.001] [Citation(s) in RCA: 196] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Revised: 12/26/2014] [Accepted: 01/05/2015] [Indexed: 12/13/2022]
Abstract
Most autoimmune diseases (AID) are linked to an imbalance between autoreactive effector T cells (Teffs) and regulatory T cells (Tregs). While blocking Teffs with immunosuppression has long been the only therapeutic option, activating/expanding Tregs may achieve the same objective without the toxicity of immunosuppression. We showed that low-dose interleukin-2 (ld-IL-2) safely expands/activates Tregs in patients with AID, such HCV-induced vasculitis and Type 1 Diabetes (T1D). Here we analyzed the kinetics and dose-relationship of IL-2 effects on immune responses in T1D patients. Ld-IL-2 therapy induced a dose-dependent increase in CD4(+)Foxp3(+) and CD8(+)Foxp3(+) Treg numbers and proportions, the duration of which was markedly dose-dependent. Tregs expressed enhanced levels of activation markers, including CD25, GITR, CTLA-4 and basal pSTAT5, and retained a 20-fold higher sensitivity to IL-2 than Teff and NK cells. Plasma levels of regulatory cytokines were increased in a dose-dependent manner, while cytokines linked to Teff and Th17 inflammatory cells were mostly unchanged. Global transcriptome analyses showed a dose-dependent decrease in immune response signatures. At the highest dose, Teff responses against beta-cell antigens were suppressed in all 4 patients tested. These results inform of broader changes induced by ld-IL-2 beyond direct effects on Tregs, and relevant for further development of ld-IL-2 for therapy and prevention of T1D, and other autoimmune and inflammatory diseases.
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Affiliation(s)
- Michelle Rosenzwajg
- AP-HP, Hôpital Pitié-Salpêtrière, Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (I2B), F-75651, Paris, France; Sorbonne Université, UPMC Univ Paris 06, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France; Inserm, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France
| | - Guillaume Churlaud
- AP-HP, Hôpital Pitié-Salpêtrière, Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (I2B), F-75651, Paris, France; Sorbonne Université, UPMC Univ Paris 06, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France; Inserm, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France
| | - Roberto Mallone
- Inserm, U1016, Institut Cochin, Immunology of Diabetes Team, DeAR Lab, F-75014, Paris, France; CNRS, UMR8104, F-75014, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, F-75014, Paris, France; AP-HP, Hôpital Cochin-Port Royal, Diabetology Department, F-75014, Paris, France
| | - Adrien Six
- AP-HP, Hôpital Pitié-Salpêtrière, Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (I2B), F-75651, Paris, France; Sorbonne Université, UPMC Univ Paris 06, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France; Inserm, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France
| | - Nicolas Dérian
- AP-HP, Hôpital Pitié-Salpêtrière, Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (I2B), F-75651, Paris, France; Sorbonne Université, UPMC Univ Paris 06, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France; Inserm, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France
| | - Wahiba Chaara
- AP-HP, Hôpital Pitié-Salpêtrière, Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (I2B), F-75651, Paris, France; Sorbonne Université, UPMC Univ Paris 06, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France; Inserm, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France
| | - Roberta Lorenzon
- AP-HP, Hôpital Pitié-Salpêtrière, Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (I2B), F-75651, Paris, France; Sorbonne Université, UPMC Univ Paris 06, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France; Inserm, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France
| | - S Alice Long
- Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
| | - Jane H Buckner
- Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
| | - Georgia Afonso
- Inserm, U1016, Institut Cochin, Immunology of Diabetes Team, DeAR Lab, F-75014, Paris, France; CNRS, UMR8104, F-75014, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, F-75014, Paris, France; AP-HP, Hôpital Cochin-Port Royal, Diabetology Department, F-75014, Paris, France
| | - Hang-Phuong Pham
- ILTOO Pharma, iPEPS ICM, Hôpital Pitié Salpêtrière, 75013, Paris, France
| | - Agnès Hartemann
- AP-HP, Hôpital Pitié-Salpêtrière, Diabetology, F-75651, Paris, France
| | - Aixin Yu
- The Diabetes Research Institute, University of Miami, Miami, FL, USA; Department of Microbiology and Immunology, University of Miami, Miami, FL, USA
| | - Alberto Pugliese
- The Diabetes Research Institute, University of Miami, Miami, FL, USA; Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL, USA; Department of Microbiology and Immunology, University of Miami, Miami, FL, USA
| | - Thomas R Malek
- The Diabetes Research Institute, University of Miami, Miami, FL, USA; Department of Microbiology and Immunology, University of Miami, Miami, FL, USA
| | - David Klatzmann
- AP-HP, Hôpital Pitié-Salpêtrière, Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (I2B), F-75651, Paris, France; Sorbonne Université, UPMC Univ Paris 06, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France; Inserm, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France.
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