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Duc Nguyen H, Ardeshir A, Fonseca VA, Kim WK. Cluster of differentiation molecules in the metabolic syndrome. Clin Chim Acta 2024; 561:119819. [PMID: 38901629 DOI: 10.1016/j.cca.2024.119819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 06/12/2024] [Accepted: 06/13/2024] [Indexed: 06/22/2024]
Abstract
Metabolic syndrome (MetS) represents a significant public health concern due to its association with an increased risk of cardiovascular disease, type 2 diabetes, and other serious health conditions. Despite extensive research, the underlying molecular mechanisms contributing to MetS pathogenesis remain elusive. This review aims to provide a comprehensive overview of the molecular mechanisms linking MetS and cluster of differentiation (CD) markers, which play critical roles in immune regulation and cellular signaling. Through an extensive literature review with a systematic approach, we examine the involvement of various CD markers in MetS development and progression, including their roles in adipose tissue inflammation, insulin resistance, dyslipidemia, and hypertension. Additionally, we discuss potential therapeutic strategies targeting CD markers for the management of MetS. By synthesizing current evidence, this review contributes to a deeper understanding of the complex interplay between immune dysregulation and metabolic dysfunction in MetS, paving the way for the development of novel therapeutic interventions.
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Affiliation(s)
- Hai Duc Nguyen
- Division of Microbiology, Tulane National Primate Research Center, Tulane University, Covington, LA, USA
| | - Amir Ardeshir
- Division of Microbiology, Tulane National Primate Research Center, Tulane University, Covington, LA, USA; Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA, USA
| | - Vivian A Fonseca
- Department Endocrinology Metabolism & Diabetes, Tulane University School of Medicine, New Orleans, LA, USA
| | - Woong-Ki Kim
- Division of Microbiology, Tulane National Primate Research Center, Tulane University, Covington, LA, USA; Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA, USA.
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Ono M, Nagao M, Takeuchi H, Fukunaga E, Nagamine T, Inagaki K, Fukuda I, Iwabu M. HLA investigation in ICI-induced T1D and isolated ACTH deficiency including meta-analysis. Eur J Endocrinol 2024; 191:9-16. [PMID: 38917237 DOI: 10.1093/ejendo/lvae081] [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: 02/27/2024] [Revised: 05/01/2024] [Accepted: 06/20/2024] [Indexed: 06/27/2024]
Abstract
OBJECTIVE Widespread use of immune checkpoint inhibitors (ICIs) in cancer treatment has led to an increase in the number of reported cases of immunotherapy-related endocrinopathies. This study aimed to analyze and compare human leukocyte antigen (HLA) signatures associated with ICI-induced type 1 diabetes (ICI-T1D) and isolated adrenocorticotropic hormone deficiency (ICI-IAD) in patients with both conditions. METHODS HLA signatures were examined for their frequencies of occurrence in 22 patients with ICI-T1D without concurrent IAD, including 16 patients from nationwide reports (ICI-T1D group) and 14 patients with ICI-IAD without concurrent T1D (ICI-IAD group). The HLA signatures were also compared for their respective frequencies in 11 patients with ICI-T1D and ICI-IAD, including eight from nationwide reports (ICI-T1D/IAD group). RESULTS In the ICI-T1D group, HLA-DRB1*09:01-DQB1*03:03 and DQA1*03:02, which are in linkage disequilibrium with DRB1*09:01-DQB1*03:03 and DRB1*13:02-DQB1*06:04, were susceptible to ICI-T1D, whereas DRB1*15:02-DQB1*06:01 was protective against ICI-T1D. In the ICI-IAD group, DPB1*09:01, C*12:02-B*52:01, and DRB1*15:02-DRB1*06:01, which are in strong linkage disequilibrium, were associated with susceptibility to ICI-IAD. Moreover, DRB1*15:02-DRB1*06:01 was not detected in the ICI-T1D/IAD group. CONCLUSIONS This study revealed specific HLA signatures associated with ICI-T1D and ICI-IAD. Moreover, HLA-DRB1*15:02-DRB1*06:01, an ICI-IAD-susceptible HLA haplotype, coincides with the ICI-T1D-protective HLA haplotype, suggesting that the presence of DRB1*15:02-DRB1*06:01 may protect against the co-occurrence of T1D in patients with ICI-IAD.
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Affiliation(s)
- Mayo Ono
- Department of Endocrinology, Metabolism and Nephrology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
| | - Mototsugu Nagao
- Department of Endocrinology, Metabolism and Nephrology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
| | - Haruki Takeuchi
- Department of Endocrinology, Metabolism and Nephrology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
| | - Etsuya Fukunaga
- Department of Endocrinology, Metabolism and Nephrology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
| | - Tomoko Nagamine
- Department of Endocrinology, Metabolism and Nephrology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
| | - Kyoko Inagaki
- Department of Endocrinology, Metabolism and Nephrology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
| | - Izumi Fukuda
- Department of Endocrinology, Metabolism and Nephrology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
| | - Masato Iwabu
- Department of Endocrinology, Metabolism and Nephrology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
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Zhang W, Chen J, Bi J, Ding N, Chen X, Wang Z, Jiao Y. Combined diabetic ketoacidosis and hyperosmolar hyperglycemic state in type 1 diabetes mellitus induced by immune checkpoint inhibitors: Underrecognized and underreported emergency in ICIs-DM. Front Endocrinol (Lausanne) 2023; 13:1084441. [PMID: 36686495 PMCID: PMC9846077 DOI: 10.3389/fendo.2022.1084441] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 12/14/2022] [Indexed: 01/05/2023] Open
Abstract
Background Combined diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) secondary to immune checkpoint inhibitors (ICIs) is extremely rarely reported among ICIs- diabetes mellitus (DM) cases and is always ignored by physicians. This study aimed to conduct a systematic review to recognize better the rare adverse event of combined DKA-HHS associated with immune checkpoints. Methods A electronic search in Pubmed/Cochrane/Web of Science, complemented by manual searches in article references, was conducted to identify clinical features of ICIs-combined DKA-HHS. Results we identified 106 patients with ICIs- type 1 diabetes mellitus (T1DM) from 82 publications: 9 patients presented a coexistence of metabolic acidosis, severe hyperglycemia, and/or DKA; All patients were not diagnosed as combined DKA-HHS. Compared with ICIs-DKA patients, combined DKA-HHS cases were prone to higher hyperglycemia (1020 ± 102.5 vs 686.7 ± 252.6mg/dL). Moreover, acute kidney injury (87.5% vs 28.6%) and prior chemotherapy (66.7% vs 31.6%) showed higher occurrences with the onset of ICIs-HHS or combined DKA-HHS.B. Conclusions Combined DKA-HHS portends a poor diagnosis in patients with coexistence features of DKA and HHS, which healthcare professionals and patients should be aware of due to differences in treatment. Our observational retrospective case series shows that patients with more risk factors were more likely to develop combined DKA-HHS. We are the first to report this group of patients' clinical characteristics and outcomes.
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Affiliation(s)
- Wenjing Zhang
- Department of Pharmacy, Shanghai Changhai Hospital, the First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Jiexiu Chen
- Department of Pharmacy, Shanghai Changhai Hospital, the First Affiliated Hospital of Naval Medical University, Shanghai, China
- Department of Clinical Pharmacy, Sichuan Provincial Maternity and Child Health Care Hospital, Affiliated Women’s and Children’s Hospital of Chengdu Medical College, Chengdu Medical College, Chengdu, China
| | - Juan Bi
- Department of Pharmacy, Shanghai Changhai Hospital, the First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Nan Ding
- Department of Pharmacy, Shanghai Changhai Hospital, the First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Xin Chen
- Department of Pharmacy, Anhui Provincial Corps Hospital, Chinese Peoples Armed Police Force, Hefei, China
| | - Zhuo Wang
- Department of Pharmacy, Shanghai Changhai Hospital, the First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Yang Jiao
- Department of Respiratory and Critical Care Medicine, Shanghai Changhai Hospital, the First Affiliated Hospital of Naval Medical University, Shanghai, China
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Krentz NAJ, Shea LD, Huising MO, Shaw JAM. Restoring normal islet mass and function in type 1 diabetes through regenerative medicine and tissue engineering. Lancet Diabetes Endocrinol 2021; 9:708-724. [PMID: 34480875 PMCID: PMC10881068 DOI: 10.1016/s2213-8587(21)00170-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 05/17/2021] [Accepted: 06/08/2021] [Indexed: 02/09/2023]
Abstract
Type 1 diabetes is characterised by autoimmune-mediated destruction of pancreatic β-cell mass. With the advent of insulin therapy a century ago, type 1 diabetes changed from a progressive, fatal disease to one that requires lifelong complex self-management. Replacing the lost β-cell mass through transplantation has proven successful, but limited donor supply and need for lifelong immunosuppression restricts widespread use. In this Review, we highlight incremental advances over the past 20 years and remaining challenges in regenerative medicine approaches to restoring β-cell mass and function in type 1 diabetes. We begin by summarising the role of endocrine islets in glucose homoeostasis and how this is altered in disease. We then discuss the potential regenerative capacity of the remaining islet cells and the utility of stem cell-derived β-like cells to restore β-cell function. We conclude with tissue engineering approaches that might improve the engraftment, function, and survival of β-cell replacement therapies.
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Affiliation(s)
- Nicole A J Krentz
- Division of Endocrinology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
| | - Lonnie D Shea
- Departments of Biomedical Engineering, Chemical Engineering, and Surgery, College of Engineering and School of Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Mark O Huising
- Department of Neurobiology, Physiology and Behavior, College of Biological Sciences, University of California, Davis, Davis, CA, USA; Department of Physiology and Membrane Biology, School of Medicine, University of California, Davis, Davis, CA, USA
| | - James A M Shaw
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK; Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
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Yim C, Mansell K, Hussein N, Arnason T. Current cancer therapies and their influence on glucose control. World J Diabetes 2021; 12:1010-1025. [PMID: 34326951 PMCID: PMC8311484 DOI: 10.4239/wjd.v12.i7.1010] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 04/11/2021] [Accepted: 06/25/2021] [Indexed: 02/06/2023] Open
Abstract
This review focuses on the development of hyperglycemia arising from widely used cancer therapies spanning four drug classes. These groups of medications were selected due to their significant association with new onset hyperglycemia, or of potentially severe clinical consequences when present. These classes include glucocorticoids that are frequently used in addition to chemotherapy treatments, and the antimetabolite class of 5-fluorouracil-related drugs. Both of these classes have been in use in cancer therapy since the 1950s. Also considered are the phosphatidyl inositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)-inhibitors that provide cancer response advantages by disrupting cell growth, proliferation and survival signaling pathways, and have been in clinical use as early as 2007. The final class to be reviewed are the monoclonal antibodies selected to function as immune checkpoint inhibitors (ICIs). These were first used in 2011 for advanced melanoma and are rapidly becoming widely utilized in many solid tumors. For each drug class, the literature has been reviewed to answer relevant questions about these medications related specifically to the characteristics of the hyperglycemia that develops with use. The incidence of new glucose elevations in euglycemic individuals, as well as glycemic changes in those with established diabetes has been considered, as has the expected onset of hyperglycemia from their first use. This comparison emphasizes that some classes exhibit very immediate impacts on glucose levels, whereas other classes can have lengthy delays of up to 1 year. A comparison of the spectrum of severity of hyperglycemic consequences stresses that the appearance of diabetic ketoacidosis is rare for all classes except for the ICIs. There are distinct differences in the reversibility of glucose elevations after treatment is stopped, as the mTOR inhibitors and ICI classes have persistent hyperglycemia long term. These four highlighted drug categories differ in their underlying mechanisms driving hyperglycemia, with clinical presentations ranging from potent yet transient insulin resistant states [type 2 diabetes mellitus (T2DM) -like] to rare permanent insulin-deficient causes of hyperglycemia. Knowledge of the relative incidence of new onset hyperglycemia and the underlying causes are critical to appreciate how and when to best screen and treat patients taking any of these cancer drug therapies.
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Affiliation(s)
- Carly Yim
- Department of Medicine, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada
| | - Kerry Mansell
- College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon S7N 5E5, Saskatchewan, Canada
| | - Nassrein Hussein
- Department of Medicine, Division of Endocrinology, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada
| | - Terra Arnason
- Departments of Anatomy and Cell Biology and Medicine, Division of Endocrinology, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada
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Kyriacou A, Melson E, Chen W, Kempegowda P. Is immune checkpoint inhibitor-associated diabetes the same as fulminant type 1 diabetes mellitus? Clin Med (Lond) 2021; 20:417-423. [PMID: 32675150 DOI: 10.7861/clinmed.2020-0054] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Pembrolizumab is an anti-cancer drug that targets programmed cell death protein-1 (PD-1) receptors on lymphocytes resulting in their activation against tumour cells. PD-1 receptors are also interspersed in endocrine organs and pembrolizumab use has long been associated with hypophysitis and thyroiditis. Since the introduction of immune checkpoint inhibitors (ICI), several cases of fulminant type 1 diabetes mellitus (FT1DM) have been reported. However, it is unclear if FT1DM and ICI-induced diabetes are the same pathology. We review the existing literature of ICI-induced diabetes to investigate its nature and to what extent it represents type 1A diabetes and/or FT1DM (type 1B diabetes) using an example case. Our review showed that ICI-induced diabetes may be a different entity to FT1DM. Furthermore, there is limited evidence for the management of ICI-induced T1DM. Further research into its pathophysiology will improve management and possibly prevent this burdensome complication.
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Affiliation(s)
- Angelos Kyriacou
- Centre of Endocrinology, Diabetes and Metabolism, Limassol, Cyprus
| | - Eka Melson
- Institute of Metabolism and Systems Research, Birmingham, UK and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | | | - Punith Kempegowda
- Institute of Metabolism and Systems Research, Birmingham, UK and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
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Zhai Y, Moosavi R, Chen M. Immune Checkpoints, a Novel Class of Therapeutic Targets for Autoimmune Diseases. Front Immunol 2021; 12:645699. [PMID: 33968036 PMCID: PMC8097144 DOI: 10.3389/fimmu.2021.645699] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 03/02/2021] [Indexed: 12/14/2022] Open
Abstract
Autoimmune diseases, such as multiple sclerosis and type-1 diabetes, are the outcomes of a failure of immune tolerance. Immune tolerance is sustained through interplays between two inter-dependent clusters of immune activities: immune stimulation and immune regulation. The mechanisms of immune regulation are exploited as therapeutic targets for the treatment of autoimmune diseases. One of these mechanisms is immune checkpoints (ICPs). The roles of ICPs in maintaining immune tolerance and hence suppressing autoimmunity were revealed in animal models and validated by the clinical successes of ICP-targeted therapeutics for autoimmune diseases. Recently, these roles were highlighted by the clinical discovery that the blockade of ICPs causes autoimmune disorders. Given the crucial roles of ICPs in immune tolerance, it is plausible to leverage ICPs as a group of therapeutic targets to restore immune tolerance and treat autoimmune diseases. In this review, we first summarize working mechanisms of ICPs, particularly those that have been utilized for therapeutic development. Then, we recount the agents and approaches that were developed to target ICPs and treat autoimmune disorders. These agents take forms of fusion proteins, antibodies, nucleic acids, and cells. We also review and discuss safety information for these therapeutics. We wrap up this review by providing prospects for the development of ICP-targeting therapeutics. In summary, the ever-increasing studies and results of ICP-targeting of therapeutics underscore their tremendous potential to become a powerful class of medicine for autoimmune diseases.
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Affiliation(s)
- Yujia Zhai
- Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, United States
| | - Reza Moosavi
- Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, United States
| | - Mingnan Chen
- Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, United States
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Stelmachowska-Banaś M, Czajka-Oraniec I. Management of endocrine immune-related adverse events of immune checkpoint inhibitors: an updated review. Endocr Connect 2020; 9:R207-R228. [PMID: 33064663 PMCID: PMC7576644 DOI: 10.1530/ec-20-0342] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 09/16/2020] [Indexed: 12/18/2022]
Abstract
Immune checkpoint inhibitors (ICIs) belong to a new group of anticancer drugs targeting T-cell proteins involved in the activation of immune response toward malignancies. Their introduction into clinical practice was a milestone in modern cancer treatment. However, the significant advantage of ICIs over conventional chemotherapy in terms of therapeutic efficacy is accompanied by new challenges related to specific side effects. ICI-induced immune system activation could lead to the loss of self-tolerance, presenting as autoimmune inflammation and dysfunction of various tissues and organs. Thus, the typical side effects of ICIs include immune-related adverse events (irAEs), among which endocrine irAEs, affecting numerous endocrine glands, have been commonly recognized. This review aimed to outline the current knowledge regarding ICI-induced endocrine disorders from a clinical perspective. We present updated information on the incidence and clinical development of ICI-induced endocrinopathies, including the most frequent thyroiditis and hypophysitis, the rarely observed insulin-dependent diabetes mellitus and primary adrenal insufficiency, and the recently described cases of hypoparathyroidism and lipodystrophy. Practical guidelines for monitoring, diagnosis, and treatment of ICI-related endocrine toxicities are also offered. Rising awareness of endocrine irAEs among oncologists, endocrinologists, and other health professionals caring for patients receiving ICIs could contribute to better safety and efficacy. As immunotherapy becomes widespread and approved for new types of malignancies, increased incidences of endocrine irAEs are expected in the future.
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Affiliation(s)
- Maria Stelmachowska-Banaś
- Department of Endocrinology, The Centre of Postgraduate Medical Education, Warsaw, Polska, Poland
- Correspondence should be addressed to M Stelmachowska-Banaś:
| | - Izabella Czajka-Oraniec
- Department of Endocrinology, The Centre of Postgraduate Medical Education, Warsaw, Polska, Poland
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Pan W, Zheng X, Chen G, Su L, Luo S, Wang W, Ye S, Weng J, Min Y. Nanotechnology's application in Type 1 diabetes. WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY 2020; 12:e1645. [PMID: 32558337 DOI: 10.1002/wnan.1645] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 04/17/2020] [Accepted: 04/17/2020] [Indexed: 12/16/2022]
Abstract
Type 1 diabetes mellitus (T1D) is an autoimmune disease caused by the immune system attacking islet cells. T1D, with a long prediabetes period, and the incidence of T1D increases with age during childhood and peaks at 10-14 years. And once it gets overt, it requires lifelong insulin replace treatment. Therefore, the diagnosis of early-stage T1D and effective treatments are important for the management of T1D patients. The imaging methods, such as magnetic resonance imaging (MRI) and so on, were applied in diagnosis of the early stage T1D and its development tracking. The addition of nanomaterials, especially in MRI, can improve the quality of T1D imaging for the diagnosis of T1D at early stage and cause less harm to human body. Meantime, among various treatment options, islet transplantation and immunotherapy are promising, effective, and less independent on insulin. The addition of nanotechnology can effectively reduce the attack of the immune system on drugs and cells, making the therapeutic drug more targeted in the body and prolonging the action time between drugs and cells, thus its addition makes these therapy safer and more efficient. In this review, we attempt to summarize the recent advances in the development of nanotechnology advances of T1D including using nanomaterials for the diagnosis and immunological imaging of T1D, protecting the transplanted islet cells from immune system attack, and delivering relevant molecules to targeted immunocytes. This article is categorized under: Diagnostic Tools > in vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Emerging Technologies Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement.
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Affiliation(s)
- Wen Pan
- Department of Endocrinology, The First Affiliated Hospital of USTC, Anhui Provincial Hospital, University of Science and Technology of China, Hefei, China.,CAS Key Lab of Soft Matter Chemistry, University of Science and Technology of China, Hefei, China.,Department of Chemistry, University of Science and Technology of China, Hefei, China
| | - Xueying Zheng
- Department of Endocrinology, The First Affiliated Hospital of USTC, Anhui Provincial Hospital, University of Science and Technology of China, Hefei, China
| | - Guiyuan Chen
- Department of Endocrinology, The First Affiliated Hospital of USTC, Anhui Provincial Hospital, University of Science and Technology of China, Hefei, China.,CAS Key Lab of Soft Matter Chemistry, University of Science and Technology of China, Hefei, China.,Department of Chemistry, University of Science and Technology of China, Hefei, China
| | - Lanhong Su
- Department of Endocrinology, The First Affiliated Hospital of USTC, Anhui Provincial Hospital, University of Science and Technology of China, Hefei, China.,CAS Key Lab of Soft Matter Chemistry, University of Science and Technology of China, Hefei, China.,Department of Chemistry, University of Science and Technology of China, Hefei, China
| | - Sihui Luo
- Department of Endocrinology, The First Affiliated Hospital of USTC, Anhui Provincial Hospital, University of Science and Technology of China, Hefei, China
| | - Wei Wang
- Department of Endocrinology, The First Affiliated Hospital of USTC, Anhui Provincial Hospital, University of Science and Technology of China, Hefei, China
| | - Shandong Ye
- Department of Endocrinology, The First Affiliated Hospital of USTC, Anhui Provincial Hospital, University of Science and Technology of China, Hefei, China
| | - Jianping Weng
- Department of Endocrinology, The First Affiliated Hospital of USTC, Anhui Provincial Hospital, University of Science and Technology of China, Hefei, China.,Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yuanzeng Min
- Department of Endocrinology, The First Affiliated Hospital of USTC, Anhui Provincial Hospital, University of Science and Technology of China, Hefei, China.,CAS Key Lab of Soft Matter Chemistry, University of Science and Technology of China, Hefei, China.,Department of Chemistry, University of Science and Technology of China, Hefei, China.,Department of Bio-X Interdisciplinary Science at Hefei National Laboratory (HFNL) for Physical Science at the Microscale, University of Science and Technology of China, Hefei, China
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de Filette JMK, Pen JJ, Decoster L, Vissers T, Bravenboer B, Van der Auwera BJ, Gorus FK, Roep BO, Aspeslagh S, Neyns B, Velkeniers B, Kharagjitsingh AV. Immune checkpoint inhibitors and type 1 diabetes mellitus: a case report and systematic review. Eur J Endocrinol 2019; 181:363-374. [PMID: 31330498 PMCID: PMC6709545 DOI: 10.1530/eje-19-0291] [Citation(s) in RCA: 173] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 07/19/2019] [Indexed: 12/16/2022]
Abstract
OBJECTIVE To better define the rare adverse event (AE) of diabetes mellitus associated with immune checkpoint inhibitors (ICIs). DESIGN AND METHODS We report the case of a lung cancer patient with diabetic ketoacidosis (DKA) and autoimmune thyroiditis during pembrolizumab treatment. We provide a systematic review of all published cases (PubMed/Web of Science/Cochrane, through November 2018) of autoimmune diabetes mellitus related to blockade of the cytotoxic T-lymphocyte antigen 4 (CTLA-4)-, programmed cell death 1 (PD-1) receptor or its ligand (PD-L1) or combination (ICI) therapy. RESULTS Our literature search identified 90 patient cases (our case excluded). Most patients were treated with anti-PD-1 or anti-PD-L1 as monotherapy (79%) or in combination with CTLA-4 blockade (15%). On average, diabetes mellitus was diagnosed after 4.5 cycles; earlier for combination ICI at 2.7 cycles. Early-onset diabetes mellitus (after one or two cycles) was observed during all treatment regimens. Diabetic ketoacidosis was present in 71%, while elevated lipase levels were detected in 52% (13/25). Islet autoantibodies were positive in 53% of patients with a predominance of glutamic acid decarboxylase antibodies. Susceptible HLA genotypes were present in 65% (mostly DR4). Thyroid dysfunction was the most frequent other endocrine AE at 24% incidence in this patient population. CONCLUSION ICI-related diabetes mellitus is a rare but often life-threatening metabolic urgency of which health-care professionals and patients should be aware. Close monitoring of blood glucose and prompt endocrine investigation in case of hyperglycemia is advisable. Predisposing factors such as HLA genotype might explain why some individuals are at risk.
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Affiliation(s)
| | - Joeri J Pen
- Diabetes Clinic, Universitair Ziekenhuis Brussel, Brussels, Belgium
| | - Lore Decoster
- Department of Medical Oncology, Universitair Ziekenhuis Brussel, Brussels, Belgium
| | - Thomas Vissers
- Medical Library, Haaglanden Medical Center, Hague, The Netherlands
| | - Bert Bravenboer
- Department of Endocrinology, Universitair Ziekenhuis Brussel, Brussels, Belgium
| | | | - Frans K Gorus
- Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
| | - Bart O Roep
- Department of Immunohematology & Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
- Department of Diabetes Immunology, Diabetes & Metabolism Research Institute, City of Hope, Duarte, California, USA
| | - Sandrine Aspeslagh
- Department of Medical Oncology, Universitair Ziekenhuis Brussel, Brussels, Belgium
| | - Bart Neyns
- Department of Medical Oncology, Universitair Ziekenhuis Brussel, Brussels, Belgium
| | - Brigitte Velkeniers
- Department of Endocrinology, Universitair Ziekenhuis Brussel, Brussels, Belgium
| | - Aan V Kharagjitsingh
- Department of Endocrinology, Universitair Ziekenhuis Brussel, Brussels, Belgium
- Diabetes Clinic, Universitair Ziekenhuis Brussel, Brussels, Belgium
- Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
- Section Endocrinology, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
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Navigating Two Roads to Glucose Normalization in Diabetes: Automated Insulin Delivery Devices and Cell Therapy. Cell Metab 2019; 29:545-563. [PMID: 30840911 DOI: 10.1016/j.cmet.2019.02.007] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 02/12/2019] [Accepted: 02/13/2019] [Indexed: 12/23/2022]
Abstract
Incredible strides have been made since the discovery of insulin almost 100 years ago. Insulin formulations have improved dramatically, glucose levels can be measured continuously, and recently first-generation biomechanical "artificial pancreas" systems have been approved by regulators around the globe. However, still only a small fraction of patients with diabetes achieve glycemic goals. Replacement of insulin-producing cells via transplantation shows significant promise, but is limited in application due to supply constraints (cadaver-based) and the need for chronic immunosuppression. Over the past decade, significant progress has been made to address these barriers to widespread implementation of a cell therapy. Can glucose levels in people with diabetes be normalized with artificial pancreas systems or via cell replacement approaches? Here we review the road ahead, including the challenges and opportunities of both approaches.
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12
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Johannesson B, Sui L, Freytes DO, Creusot RJ, Egli D. Toward beta cell replacement for diabetes. EMBO J 2015; 34:841-55. [PMID: 25733347 DOI: 10.15252/embj.201490685] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Accepted: 01/22/2015] [Indexed: 12/31/2022] Open
Abstract
The discovery of insulin more than 90 years ago introduced a life-saving treatment for patients with type 1 diabetes, and since then, significant progress has been made in clinical care for all forms of diabetes. However, no method of insulin delivery matches the ability of the human pancreas to reliably and automatically maintain glucose levels within a tight range. Transplantation of human islets or of an intact pancreas can in principle cure diabetes, but this approach is generally reserved for cases with simultaneous transplantation of a kidney, where immunosuppression is already a requirement. Recent advances in cell reprogramming and beta cell differentiation now allow the generation of personalized stem cells, providing an unlimited source of beta cells for research and for developing autologous cell therapies. In this review, we will discuss the utility of stem cell-derived beta cells to investigate the mechanisms of beta cell failure in diabetes, and the challenges to develop beta cell replacement therapies. These challenges include appropriate quality controls of the cells being used, the ability to generate beta cell grafts of stable cellular composition, and in the case of type 1 diabetes, protecting implanted cells from autoimmune destruction without compromising other aspects of the immune system or the functionality of the graft. Such novel treatments will need to match or exceed the relative safety and efficacy of available care for diabetes.
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Affiliation(s)
| | - Lina Sui
- Naomi Berrie Diabetes Center & Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Donald O Freytes
- The New York Stem Cell Foundation Research Institute, New York, NY, USA
| | - Remi J Creusot
- Columbia Center for Translational Immunology, Department of Medicine and Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA
| | - Dieter Egli
- The New York Stem Cell Foundation Research Institute, New York, NY, USA Naomi Berrie Diabetes Center & Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY, USA
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13
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Li R, Lee J, Kim MS, Liu V, Moulik M, Li H, Yi Q, Xie A, Chen W, Yang L, Li Y, Tsai TH, Oka K, Chan L, Yechoor V. PD-L1-driven tolerance protects neurogenin3-induced islet neogenesis to reverse established type 1 diabetes in NOD mice. Diabetes 2015; 64:529-40. [PMID: 25332429 PMCID: PMC4303975 DOI: 10.2337/db13-1737] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
A breakdown in self-tolerance underlies autoimmune destruction of β-cells and type 1 diabetes. A cure by restoring β-cell mass is limited by the availability of transplantable β-cells and the need for chronic immunosuppression. Evidence indicates that inhibiting costimulation through the PD-1/PD-L1 pathway is central to immune tolerance. We therefore tested whether induction of islet neogenesis in the liver, protected by PD-L1-driven tolerance, reverses diabetes in NOD mice. We demonstrated a robust induction of neo-islets in the liver of diabetic NOD mice by gene transfer of Neurogenin3, the islet-defining factor, along with betacellulin, an islet growth factor. These neo-islets expressed all the major pancreatic hormones and transcription factors. However, an enduring restoration of glucose-stimulated insulin secretion and euglycemia occurs only when tolerance is also induced by the targeted overexpression of PD-L1 in the neo-islets, which results in inhibition of proliferation and increased apoptosis of infiltrating CD4(+) T cells. Further analysis revealed an inhibition of cytokine production from lymphocytes isolated from the liver but not from the spleen of treated mice, indicating that treatment did not result in generalized immunosuppression. This treatment strategy leads to persistence of functional neo-islets that resist autoimmune destruction and consequently an enduring reversal of diabetes in NOD mice.
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Affiliation(s)
- Rongying Li
- Division of Diabetes, Endocrinology and Metabolism, Diabetes and Endocrinology Research Center, and Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Jeongkyung Lee
- Division of Diabetes, Endocrinology and Metabolism, Diabetes and Endocrinology Research Center, and Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Mi-sun Kim
- Division of Diabetes, Endocrinology and Metabolism, Diabetes and Endocrinology Research Center, and Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Victoria Liu
- Division of Diabetes, Endocrinology and Metabolism, Diabetes and Endocrinology Research Center, and Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Mousumi Moulik
- Division of Cardiology, Department of Pediatrics, University of Texas Medical School at Houston, Houston, TX
| | - Haiyan Li
- Department of Cancer Biology, Cleveland Clinic, Lerner Research Institute, Cleveland, OH
| | - Qing Yi
- Department of Cancer Biology, Cleveland Clinic, Lerner Research Institute, Cleveland, OH
| | - Aini Xie
- Division of Diabetes, Endocrinology and Metabolism, Diabetes and Endocrinology Research Center, and Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Wenhao Chen
- Division of Diabetes, Endocrinology and Metabolism, Diabetes and Endocrinology Research Center, and Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Lina Yang
- Division of Diabetes, Endocrinology and Metabolism, Diabetes and Endocrinology Research Center, and Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Yimin Li
- Division of Diabetes, Endocrinology and Metabolism, Diabetes and Endocrinology Research Center, and Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Tsung Huang Tsai
- Division of Diabetes, Endocrinology and Metabolism, Diabetes and Endocrinology Research Center, and Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Kazuhiro Oka
- Division of Diabetes, Endocrinology and Metabolism, Diabetes and Endocrinology Research Center, and Department of Medicine, Baylor College of Medicine, Houston, TX Division of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
| | - Lawrence Chan
- Division of Diabetes, Endocrinology and Metabolism, Diabetes and Endocrinology Research Center, and Department of Medicine, Baylor College of Medicine, Houston, TX Division of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
| | - Vijay Yechoor
- Division of Diabetes, Endocrinology and Metabolism, Diabetes and Endocrinology Research Center, and Department of Medicine, Baylor College of Medicine, Houston, TX Division of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
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14
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Bhattacharya P, Fan J, Haddad C, Essani A, Gopisetty A, Elshabrawy HA, Vasu C, Prabhakar BS. A novel pancreatic β-cell targeting bispecific-antibody (BsAb) can prevent the development of type 1 diabetes in NOD mice. Clin Immunol 2014; 153:187-98. [PMID: 24792135 DOI: 10.1016/j.clim.2014.04.014] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Revised: 04/13/2014] [Accepted: 04/24/2014] [Indexed: 11/26/2022]
Abstract
To prepare a novel Bispecific Antibody (BsAb) as a potential targeted therapy for T1D, we produced a "functionally inert" monoclonal antibody (mAb) against Glucose transporter-2 (GLUT-2) expressed on β-cells to serve as an anchoring antibody. The therapeutic arm is an agonistic mAb against Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4), a negative regulator of T-cell activation expressed on activated CD4+ T-cells. A BsAb was prepared by chemically coupling an anti-GLUT2 mAb to an agonistic anti-CTLA-4 mAb. This BsAb was able to bind to GLUT2 and CTLA-4 in vitro, and to pancreatic islets, both in vitro and in vivo. We tested the safety and efficacy of this BsAb by treating Non-Obese Diabetes (NOD) mice and found that it could delay the onset of diabetes with no apparent undesirable side effects. Thus, engagement of CTLA-4 on activated T cells from target tissue can be an effective way to treat type-1 diabetes.
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Affiliation(s)
- Palash Bhattacharya
- Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 606012, USA
| | - Jilao Fan
- Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 606012, USA
| | - Christine Haddad
- Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 606012, USA
| | - Abdul Essani
- Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 606012, USA
| | - Anupama Gopisetty
- Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 606012, USA
| | - Hatem A Elshabrawy
- Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 606012, USA
| | - Chenthamarakshan Vasu
- Department of Surgery, Hollings Cancer Centre, College of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Bellur S Prabhakar
- Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 606012, USA.
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15
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Lin MH, Yeh LT, Chen SJ, Chiou HYC, Chu CC, Yen LB, Lin KI, Chang DM, Sytwu HK. T cell-specific BLIMP-1 deficiency exacerbates experimental autoimmune encephalomyelitis in nonobese diabetic mice by increasing Th1 and Th17 cells. Clin Immunol 2014; 151:101-13. [PMID: 24568746 DOI: 10.1016/j.clim.2014.02.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Revised: 02/07/2014] [Accepted: 02/08/2014] [Indexed: 01/07/2023]
Abstract
Recently, we demonstrated that B lymphocyte-induced maturation protein 1 (BLIMP-1) has a role in regulating the differentiation and effector function of Th1 and Th17 cells. As these cells play critical roles in the induction and pathogenesis of experimental autoimmune encephalomyelitis (EAE), we investigated the potential role of T cell BLIMP-1 in modulating MOG35-55-induced EAE. We established T cell-specific BLIMP-1 conditional knockout (CKO) NOD mice to dissect the role of BLIMP-1 in EAE using loss-of-function model. Our results indicate that EAE severity is dramatically exacerbated in CKO mice. The numbers of CNS-infiltrating Th1, Th17, IFN-γ(+)IL-17A(+), and IL-21(+)IL-17A(+) CD4(+) T cells are remarkably increased in brain and spinal cord of CKO mice. Moreover, the ratio of Tregs/effectors and IL-10 production of Tregs are significantly downregulated in CNS of CKO mice. We conclude that BLIMP-1 suppresses autoimmune encephalomyelitis via downregulating Th1 and Th17 cells and impairing Treg cells.
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Affiliation(s)
- Ming-Hong Lin
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Li-Tzu Yeh
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Shyi-Jou Chen
- Department of Pediatrics, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Hsin-Ying C Chiou
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Chin-Chen Chu
- Department of Anesthesiology, Chi Mei Medical Center, Tainan, Taiwan, ROC; Department of Recreation and Health-Care Management, Chia Nan University of Pharmacy and Science, Tainan, Taiwan, ROC.
| | - Linju B Yen
- Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan, ROC
| | - Kuo-I Lin
- Genomics Research Center, Academia Sinica, Taipei, Taiwan, ROC
| | - Deh-Ming Chang
- Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Huey-Kang Sytwu
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan, ROC; Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, ROC.
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16
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Lin YC, Chen BM, Lu WC, Su CI, Prijovich ZM, Chung WC, Wu PY, Chen KC, Lee IC, Juan TY, Roffler SR. The B7-1 cytoplasmic tail enhances intracellular transport and mammalian cell surface display of chimeric proteins in the absence of a linear ER export motif. PLoS One 2013; 8:e75084. [PMID: 24073236 PMCID: PMC3779271 DOI: 10.1371/journal.pone.0075084] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2013] [Accepted: 08/12/2013] [Indexed: 11/18/2022] Open
Abstract
Membrane-tethered proteins (mammalian surface display) are increasingly being used for novel therapeutic and biotechnology applications. Maximizing surface expression of chimeric proteins on mammalian cells is important for these applications. We show that the cytoplasmic domain from the B7-1 antigen, a commonly used element for mammalian surface display, can enhance the intracellular transport and surface display of chimeric proteins in a Sar1 and Rab1 dependent fashion. However, mutational, alanine scanning and deletion analysis demonstrate the absence of linear ER export motifs in the B7 cytoplasmic domain. Rather, efficient intracellular transport correlated with the presence of predicted secondary structure in the cytoplasmic tail. Examination of the cytoplasmic domains of 984 human and 782 mouse type I transmembrane proteins revealed that many previously identified ER export motifs are rarely found in the cytoplasmic tail of type I transmembrane proteins. Our results suggest that efficient intracellular transport of B7 chimeric proteins is associated with the structure rather than to the presence of a linear ER export motif in the cytoplasmic tail, and indicate that short (less than ~ 10-20 amino acids) and unstructured cytoplasmic tails should be avoided to express high levels of chimeric proteins on mammalian cells.
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Affiliation(s)
- Yi-Chieh Lin
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Bing-Mae Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Wei-Cheng Lu
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Chien-I Su
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | | | - Wen-Chuan Chung
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Pei-Yu Wu
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Kai-Chuan Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - I-Chiao Lee
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Ting-Yi Juan
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Steve R. Roffler
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
- * E-mail:
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17
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Zóka A, Műzes G, Somogyi A, Varga T, Szémán B, Al-Aissa Z, Hadarits O, Firneisz G. Altered immune regulation in type 1 diabetes. Clin Dev Immunol 2013; 2013:254874. [PMID: 24285974 PMCID: PMC3763577 DOI: 10.1155/2013/254874] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2013] [Revised: 06/19/2013] [Accepted: 07/04/2013] [Indexed: 02/05/2023]
Abstract
Research in genetics and immunology was going on separate strands for a long time. Type 1 diabetes mellitus might not be characterized with a single pathogenetic factor. It develops when a susceptible individual is exposed to potential triggers in a given sequence and timeframe that eventually disarranges the fine-tuned immune mechanisms that keep autoimmunity under control in health. Genomewide association studies have helped to understand the congenital susceptibility, and hand-in-hand with the immunological research novel paths of immune dysregulation were described in central tolerance, apoptotic pathways, or peripheral tolerance mediated by regulatory T-cells. Epigenetic factors are contributing to the immune dysregulation. The interplay between genetic susceptibility and potential triggers is likely to play a role at a very early age and gradually results in the loss of balanced autotolerance and subsequently in the development of the clinical disease. Genetic susceptibility, the impaired elimination of apoptotic β -cell remnants, altered immune regulatory functions, and environmental factors such as viral infections determine the outcome. Autoreactivity might exist under physiologic conditions and when the integrity of the complex regulatory process is damaged the disease might develop. We summarized the immune regulatory mechanisms that might have a crucial role in disease pathology and development.
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Affiliation(s)
- András Zóka
- Second Department of Medicine, Semmelweis University, Szentkirályi Street 46, Budapest 1088, Hungary
| | - Györgyi Műzes
- Second Department of Medicine, Semmelweis University, Szentkirályi Street 46, Budapest 1088, Hungary
| | - Anikó Somogyi
- Second Department of Medicine, Semmelweis University, Szentkirályi Street 46, Budapest 1088, Hungary
| | - Tímea Varga
- Second Department of Medicine, Semmelweis University, Szentkirályi Street 46, Budapest 1088, Hungary
| | - Barbara Szémán
- Second Department of Medicine, Semmelweis University, Szentkirályi Street 46, Budapest 1088, Hungary
| | - Zahra Al-Aissa
- Second Department of Medicine, Semmelweis University, Szentkirályi Street 46, Budapest 1088, Hungary
| | - Orsolya Hadarits
- First Department of Obstetrics and Gynecology, Semmelweis University, Baross Street 27, Budapest 1085, Hungary
| | - Gábor Firneisz
- Second Department of Medicine, Semmelweis University, Szentkirályi Street 46, Budapest 1088, Hungary
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18
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Lin MH, Chou FC, Yeh LT, Fu SH, Chiou HYC, Lin KI, Chang DM, Sytwu HK. B lymphocyte-induced maturation protein 1 (BLIMP-1) attenuates autoimmune diabetes in NOD mice by suppressing Th1 and Th17 cells. Diabetologia 2013; 56:136-46. [PMID: 23052053 DOI: 10.1007/s00125-012-2722-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2012] [Accepted: 08/14/2012] [Indexed: 10/27/2022]
Abstract
AIMS/HYPOTHESIS Recent reports indicate that B lymphocyte-induced maturation protein 1 (BLIMP-1), encoded by the Prdm1 gene, expands its control over T cells and is associated with susceptibility to colitis in mice with T cell-specific BLIMP-1 deficiency. In this study, we aimed to investigate the potential role of BLIMP-1 in regulating autoimmune diabetes and T helper type 17 (Th17) cells. METHODS We generated T cell-specific Blimp1 (also known as Prdm1) transgenic (Tg) or conditional knockout (CKO) NOD mice, in which Blimp1 is overexpressed or deleted in T cells, respectively. By side-by-side analysing these Tg or CKO mice, we further dissected the potential mechanisms of BLIMP-1-mediated modulation on autoimmune diabetes. RESULTS Overproduction of BLIMP-1 in T cells significantly attenuated insulitis and the incidence of diabetes in NOD mice. Consistent with these results, the diabetogenic effect of splenocytes was remarkably impaired in Blimp1 Tg mice. Moreover, overproduction of BLIMP-1 repressed the proliferation and activation of lymphocytes and enhanced the function of regulatory T cells (Tregs) in NOD mice. In contrast, mice lacking BLIMP-1 in T cells markedly increased Th1 and Th17 cells, and developed highly proliferative and activated lymphocytes. Strikingly, overexpansion of Th1 and Th17 cells in CKO mice was significantly reduced by introducing a Blimp1 transgene, reinforcing the emerging role of BLIMP-1 in autoimmunity. CONCLUSIONS/INTERPRETATION We conclude that BLIMP-1 orchestrates a T cell-specific modulation of autoimmunity by affecting lymphocyte proliferation and activation, Th1 and Th17 cell differentiation, and Treg function. Our results provide a theoretical basis for developing BLIMP-1-manipulated therapies for autoimmune diabetes.
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MESH Headings
- Animals
- Autoimmunity
- Cell Differentiation
- Cell Proliferation
- Cells, Cultured
- Crosses, Genetic
- Diabetes Mellitus, Type 1/immunology
- Diabetes Mellitus, Type 1/metabolism
- Diabetes Mellitus, Type 1/pathology
- Diabetes Mellitus, Type 1/prevention & control
- Female
- Immunosuppression Therapy
- Lymphocyte Activation
- Male
- Mice
- Mice, Inbred NOD
- Mice, Knockout
- Mice, SCID
- Mice, Transgenic
- Pancreas/immunology
- Pancreas/pathology
- Positive Regulatory Domain I-Binding Factor 1
- Specific Pathogen-Free Organisms
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/pathology
- Th1 Cells/immunology
- Th1 Cells/pathology
- Th17 Cells/immunology
- Th17 Cells/pathology
- Transcription Factors/biosynthesis
- Transcription Factors/genetics
- Transcription Factors/metabolism
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Affiliation(s)
- M-H Lin
- Graduate Institute of Medical Sciences, National Defense Medical Center, 161, Section 6, MinChuan East Road, Neihu, Taipei 114, Taiwan, Republic of China
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19
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Chou FC, Chen HY, Chen SJ, Fang MC, Sytwu HK. Rodent models for investigating the dysregulation of immune responses in type 1 diabetes. J Diabetes Res 2013; 2013:138412. [PMID: 23671851 PMCID: PMC3647569 DOI: 10.1155/2013/138412] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2012] [Accepted: 02/07/2013] [Indexed: 12/02/2022] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease mediated by T cells that selectively destroy the insulin-producing β cells. Previous reports based on epidemiological and animal studies have demonstrated that both genetic factors and environmental parameters can either promote or attenuate the progression of autoimmunity. In recent decades, several inbred rodent strains that spontaneously develop diabetes have been applied to the investigation of the pathogenesis of T1D. Because the genetic manipulation of mice is well developed (transgenic, knockout, and conditional knockout/transgenic), most studies are performed using the nonobese diabetic (NOD) mouse model. This paper will focus on the use of genetically manipulated NOD mice to explore the pathogenesis of T1D and to develop potential therapeutic approaches.
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Affiliation(s)
- Feng-Cheng Chou
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, R8324, 161, Section 6, MinChuan East Road, Neihu, Taipei 114, Taiwan
| | - Heng-Yi Chen
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, R8324, 161, Section 6, MinChuan East Road, Neihu, Taipei 114, Taiwan
| | - Shyi-Jou Chen
- Department of Pediatrics, Tri-Service General Hospital, 325, Section 2, Chenggong Road, Neihu, Taipei 114, Taiwan
| | - Mei-Cho Fang
- Laboratory Animal Center, National Defense Medical Center, Taipei 114, Taiwan
| | - Huey-Kang Sytwu
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, R8324, 161, Section 6, MinChuan East Road, Neihu, Taipei 114, Taiwan
- *Huey-Kang Sytwu:
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20
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Chou FC, Kuo CC, Wang YL, Lin MH, Linju Yen B, Chang DM, Sytwu HK. Overexpression of galectin-9 in islets prolongs grafts survival via downregulation of Th1 responses. Cell Transplant 2012; 22:2135-2145. [PMID: 23067523 DOI: 10.3727/096368912x657891] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
The differential activation of T helper (Th) cells and production of cytokines contribute to graft rejection or tolerance. In general, the Th1-type cytokines and cytotoxic T-cells are detected consistently in a host who is undergoing rejection, whereas Th2 responses are linked to a tolerance condition. Galectin-9 modulates Th1 cell immunity by binding to the T-cell immunoglobulin mucin-3 (Tim-3) molecule expressed on the Th1 cells. We investigate whether overexpression of galectin-9 in islets prolongs grafts survival in diabetic recipients. Islets were transduced with lentiviruses carrying galectin-9 and were then transplanted to streptozotocin-induced diabetic NOD/SCID recipients. The normoglycemic recipients then received splenocytes from diabetic NOD mice. Blood glucose concentration was monitored daily after adoptive transfer. The histology of the islet grafts and flow cytometric analyses were assessed at the end of the study. Overexpression of galectin-9 in islets prolonged graft survival in NOD/SCID mice after challenge with diabetogenic splenocytes (mean graft survival, 38.5 vs. 26.0 days, n=10, respectively; p=0.0096). The galectin-9-overexpressed grafts showed decreased infiltration of IFN-γ-producing CD4(+) and CD8(+) T-cells, but not of IL-17-producing CD4(+) T-cells. Strikingly, this islet-specific genetic manipulation did not affect the systemic lymphocyte composition, indicating that galectin-9 may regulate T-cell-mediated inflammation in situ. We demonstrate that galectin-9 protects grafts from Th1 and Tc1 cell-mediated rejections, suggesting that galectin-9 has preventive and/or therapeutic benefit in transplant therapy for autoimmune diabetes and may be applied further to the transplantation of other organs or tissues.
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Affiliation(s)
- Feng-Cheng Chou
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan
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21
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Chou FC, Huang SH, Sytwu HK. Genetically engineered islets and alternative sources of insulin-producing cells for treating autoimmune diabetes: quo vadis? Int J Endocrinol 2012; 2012:296485. [PMID: 22690214 PMCID: PMC3368364 DOI: 10.1155/2012/296485] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2011] [Accepted: 03/29/2012] [Indexed: 01/29/2023] Open
Abstract
Islet transplantation is a promising therapy for patients with type 1 diabetes that can provide moment-to-moment metabolic control of glucose and allow them to achieve insulin independence. However, two major problems need to be overcome: (1) detrimental immune responses, including inflammation induced by the islet isolation/transplantation procedure, recurrence autoimmunity, and allorejection, can cause graft loss and (2) inadequate numbers of organ donors. Several gene therapy approaches and pharmaceutical treatments have been demonstrated to prolong the survival of pancreatic islet grafts in animal models; however, the clinical applications need to be investigated further. In addition, for an alternative source of pancreatic β-cell replacement therapy, the ex vivo generation of insulin-secreting cells from diverse origins of stem/progenitor cells has become an attractive option in regenerative medicine. This paper focuses on the genetic manipulation of islets during transplantation therapy and summarizes current strategies to obtain functional insulin-secreting cells from stem/progenitor cells.
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Affiliation(s)
- Feng-Cheng Chou
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Neihu, Taipei 114, Taiwan
| | - Shing-Hwa Huang
- Department of General Surgery, Tri-Service General Hospital, Taipei 114, Taiwan
| | - Huey-Kang Sytwu
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Neihu, Taipei 114, Taiwan
- *Huey-Kang Sytwu:
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Persson J, Beyer I, Yumul R, Li Z, Kiem HP, Roffler S, Lieber A. Immuno-therapy with anti-CTLA4 antibodies in tolerized and non-tolerized mouse tumor models. PLoS One 2011; 6:e22303. [PMID: 21779410 PMCID: PMC3136517 DOI: 10.1371/journal.pone.0022303] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2011] [Accepted: 06/23/2011] [Indexed: 11/23/2022] Open
Abstract
Monoclonal antibodies specific for cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA4) are a novel form of cancer immunotherapy. While preclinical studies in mouse tumor models have shown anti-tumor efficacy of anti-CTLA4 injection or expression, anti-CTLA4 treatment in patients with advanced cancers had disappointing therapeutic benefit. These discrepancies have to be addressed in more adequate pre-clinical models. We employed two tumor models. The first model is based on C57Bl/6 mice and syngeneic TC-1 tumors expressing HPV16 E6/E7. In this model, the HPV antigens are neo-antigens, against which no central tolerance exists. The second model involves mice transgenic for the proto-oncogen neu and syngeneic mouse mammary carcinoma (MMC) cells. In this model tolerance to Neu involves both central and peripheral mechanisms. Anti-CTLA4 delivery as a protein or expression from gene-modified tumor cells were therapeutically efficacious in the non-tolerized TC-1 tumor model, but had no effect in the MMC-model. We also used the two tumor models to test an immuno-gene therapy approach for anti-CTLA4. Recently, we used an approach based on hematopoietic stem cells (HSC) to deliver the relaxin gene to tumors and showed that this approach facilitates pre-existing anti-tumor T-cells to control tumor growth in the MMC tumor model. However, unexpectedly, when used for anti-CTLA4 gene delivery in this study, the HSC-based approach was therapeutically detrimental in both the TC-1 and MMC models. Anti-CTLA4 expression in these models resulted in an increase in the number of intratumoral CD1d+ NKT cells and in the expression of TGF-β1. At the same time, levels of pro-inflammatory cytokines and chemokines, which potentially can support anti-tumor T-cell responses, were lower in tumors of mice that received anti-CTLA4-HSC therapy. The differences in outcomes between the tolerized and non-tolerized models also provide a potential explanation for the low efficacy of CTLA4 blockage approaches in cancer immunotherapy trials.
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Affiliation(s)
- Jonas Persson
- Department of Medicine, University of Washington, Seattle, Washington, United States of America
| | - Ines Beyer
- Department of Medicine, University of Washington, Seattle, Washington, United States of America
| | - Roma Yumul
- Department of Medicine, University of Washington, Seattle, Washington, United States of America
| | - ZongYi Li
- Department of Medicine, University of Washington, Seattle, Washington, United States of America
| | - Hans-Peter Kiem
- Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Steve Roffler
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - André Lieber
- Department of Medicine, University of Washington, Seattle, Washington, United States of America
- Department of Pathology University of Washington, Washington, United States of America
- * E-mail:
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Huang SH, Chu CH, Yu JC, Chuang WC, Lin GJ, Chen PL, Chou FC, Chau LY, Sytwu HK. Transgenic expression of haem oxygenase-1 in pancreatic beta cells protects non-obese mice used as a model of diabetes from autoimmune destruction and prolongs graft survival following islet transplantation. Diabetologia 2010; 53:2389-400. [PMID: 20683574 DOI: 10.1007/s00125-010-1858-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2010] [Accepted: 07/05/2010] [Indexed: 01/05/2023]
Abstract
AIMS/HYPOTHESIS Haem oxygenase 1 (HO-1) has strong anti-apoptotic, anti-inflammatory and antioxidative effects that help protect cells against various forms of immune attack. We investigated whether transgenic expression of Ho-1 (also known as Hmox1) in pancreatic beta cells would protect NOD mice from autoimmune damage and prolong graft survival following islet transplantation. METHODS To evaluate the protective effect of beta cell-specific HO-1 in autoimmune diabetes, we used an insulin promoter-driven murine Ho-1 construct (pIns-mHo-1) to generate a transgenic NOD mouse. Transgene expression, insulitis and the incidence of diabetes in mice were characterised. Lymphocyte composition, the development of T helper (Th)1, Th2 and T regulatory (Treg) cells, T cell proliferation and lymphocyte-mediated disease transfer were analysed. The potential effects of transgenic islets and islet transplantation on apoptosis, inflammation and the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) were evaluated. RESULTS Transgenic mice showed less severe insulitis and a lower incidence of diabetes than non-transgenic control littermates. Lymphocyte composition and functions were not affected. Islets from transgenic mice expressed lower levels of proinflammatory cytokines/chemokines, proapoptotic gene expression and amounts of ROS/RNS, and were more resistant to TNF-α- and IFN-γ-induced apoptosis. Islet grafts from transgenic mice also survived longer in diabetic recipients than control islets. CONCLUSIONS/INTERPRETATION Transgenic overexpression of Ho-1 in beta cells protected NOD mice from diabetes and delayed the autoimmune destruction of islet grafts, providing valuable insight into the development of better strategies for clinical islet transplantation in patients with type 1 diabetes.
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Affiliation(s)
- S H Huang
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China
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Thayer TC, Wilson SB, Mathews CE. Use of nonobese diabetic mice to understand human type 1 diabetes. Endocrinol Metab Clin North Am 2010; 39:541-61. [PMID: 20723819 PMCID: PMC2925291 DOI: 10.1016/j.ecl.2010.05.001] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In 1922, Leonard Thompson received the first injections of insulin prepared from the pancreas of canine test subjects. From pancreatectomized dogs to the more recent development of animal models that spontaneously develop autoimmune syndromes, animal models have played a meaningful role in furthering diabetes research. Of these animals, the nonobese diabetic (NOD) mouse is the most widely used for research in type 1 diabetes (T1D) because the NOD shares several genetic and immunologic traits with the human form of the disease. In this article, the authors discuss the similarities and differences in NOD and human T1D and the potential role of NOD mice in future preclinical studies, aiming to provide a better understanding of the genetic and immune defects that lead to T1D.
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Affiliation(s)
- Terri C Thayer
- Department of Pathology, Immunology, and Laboratory Medicine, The University of Florida College of Medicine, Gainesville, FL 32610, USA
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