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1.
Diabetes ; 67(9): 1858-1866, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29945890

RESUMO

Indoleamine 2,3 dioxygenase-1 (IDO1) is a powerful immunoregulatory enzyme that is deficient in patients with type 1 diabetes (T1D). In this study, we present the first systematic evaluation of IDO1 expression and localization in human pancreatic tissue. Although IDO1 was constitutively expressed in ß-cells from donors without diabetes, less IDO1 was expressed in insulin-containing islets from double autoantibody-positive donors and patients with recent-onset T1D, although it was virtually absent in insulin-deficient islets from donors with T1D. Scatter plot analysis suggested that IDO1 decay occurred in individuals with multiple autoantibodies, prior to ß-cell demise. IDO1 impairment might therefore contribute to ß-cell demise and could potentially emerge as a promising therapeutic target.


Assuntos
Doenças Autoimunes/metabolismo , Autoimunidade , Diabetes Mellitus Tipo 1/metabolismo , Regulação para Baixo , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Células Secretoras de Insulina/enzimologia , Estado Pré-Diabético/metabolismo , Adolescente , Adulto , Idoso , Autoanticorpos/metabolismo , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Doenças Autoimunes/fisiopatologia , Cadáver , Estudos de Coortes , Estudos Transversais , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/fisiopatologia , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/fisiopatologia , Progressão da Doença , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Masculino , Pessoa de Meia-Idade , Estado Pré-Diabético/imunologia , Estado Pré-Diabético/patologia , Estado Pré-Diabético/fisiopatologia , Transporte Proteico , Adulto Jovem
2.
Front Immunol ; 9: 1069, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29892281

RESUMO

Obesity is associated with adipose tissue inflammation, insulin resistance, and the development of type 2 diabetes (T2D). However, our knowledge is mostly based on conventional murine models and promising preclinical studies rarely translated into successful therapies. There is a growing awareness of the limitations of studies in laboratory mice, housed in abnormally hygienic specific pathogen-free (SPF) conditions, as relevant aspects of the human immune system remain unappreciated. Here, we assessed the impact of housing conditions on adaptive immunity and metabolic disease processes during high-fat diet (HFD). We therefore compared diet-induced obesity in SPF mice with those housed in non-SPF, so-called "antigen exposed" (AE) conditions. Surprisingly, AE mice fed a HFD maintained increased insulin levels to compensate for insulin resistance, which was reflected in islet hyperplasia and improved glucose tolerance compared to SPF mice. By contrast, we observed higher proportions of effector/memory T cell subsets in blood and liver of HFD AE mice accompanied by the development of non-alcoholic steatohepatitis-like liver pathology. Thus, our data demonstrate the impact of housing conditions on metabolic alterations. Studies in AE mice, in which physiological microbial exposure was restored, could provide a tool for revealing therapeutic targets for immune-based interventions for T2D patients.

3.
Diabetes Metab Res Rev ; 34(6): e3010, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29637693

RESUMO

BACKGROUND: Oral insulin as a preventive strategy and/or treatment of type 1 diabetes has been the target of much research. Producing oral insulins is a complex and challenging task, with numerous pitfalls, due to physiological, physical, and biochemical barriers. Our aim was to determine the impact of oral insulin on the delicate gut microbiota composition. METHODS: Female nonobese diabetic mice were given oral porcine insulin 2 times a week from 5 weeks of age for 4 weeks, and then subsequently once a week for 21 weeks, or until euthanized. The mice were divided into groups on a gluten-reduced diet or a standard diet. Gut microbiota composition was analysed based on faecal samples, and the type 1 diabetes incidence of the mice was monitored. RESULTS: We observed no influence of the oral porcine insulin on the gut microbiota composition of mice on a gluten-reduced or a standard diet at 9 weeks of age. Also, the administration of oral insulin did not influence the incidence of type 1 diabetes at 30 weeks of age. CONCLUSIONS: Oral porcine insulin does not alter the gut microbiota composition of nonobese diabetic mice on either a gluten-reduced diet or standard diet. Also, the oral porcine insulin did not influence the incidence of type 1 diabetes in the groups.

5.
Sci Immunol ; 3(21)2018 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-29572238

RESUMO

The inflammatory lesion at the pancreatic islet in type 1 diabetes (T1D) contains a heterogeneous infiltrate of T cells. In human and mouse studies, a large majority (98 to 99%) of the cytotoxic CD8+ T cells (CTLs) within islets are not specific to any islet antigen and are thought to passively add to tissue damage. We show by intravital confocal microscopy the opposite, immune-regulatory function of this cohort of CTLs. Diabetes did not develop in mice with islets showing high levels of infiltration of non-islet-specific CTLs not recognizing local antigens. Accumulation of such CTLs resulted in lower activation and proliferation of islet-specific CTLs, leading them to enter a state of unresponsiveness due to limited access to antigens at the inflammatory lesion. This nonspecific suppression by nonautoreactive CTLs was recapitulated in a model of viral meningitis, may explain viral interference in autoimmunity, and provides insight into the regulation of organ-specific autoimmune responses.

6.
Cell Rep ; 22(10): 2667-2676, 2018 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-29514095

RESUMO

Many patients with type 1 diabetes (T1D) have residual ß cells producing small amounts of C-peptide long after disease onset but develop an inadequate glucagon response to hypoglycemia following T1D diagnosis. The features of these residual ß cells and α cells in the islet endocrine compartment are largely unknown, due to the difficulty of comprehensive investigation. By studying the T1D pancreas and isolated islets, we show that remnant ß cells appeared to maintain several aspects of regulated insulin secretion. However, the function of T1D α cells was markedly reduced, and these cells had alterations in transcription factors constituting α and ß cell identity. In the native pancreas and after placing the T1D islets into a non-autoimmune, normoglycemic in vivo environment, there was no evidence of α-to-ß cell conversion. These results suggest an explanation for the disordered T1D counterregulatory glucagon response to hypoglycemia.

8.
J Autoimmun ; 84: 65-74, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28711285

RESUMO

Immunotherapy for type 1 diabetes (T1D) has previously focused on suppressing the autoimmune response against pancreatic beta cells to preserve endogenous insulin production and regulate glucose levels. With increased attention toward combination therapy strategies, studies indicate the multifunctional cytokine interleukin-21 (IL-21) may be a suitable target as an immuno-modulatory arm, while glucagon-like peptide-1 receptor (GLP-1R) agonists may be appropriate as a beta cell protective arm in combination therapy for T1D. We report here that treatment with anti-IL-21 monoclonal antibody delays diabetes onset in the spontaneous non-obese diabetic (NOD) and NOD.scid adoptive transfer models, while its effect in reversing recent-onset hyperglycemia is limited. However, the combination of anti-IL-21 plus the GLP-1R agonist liraglutide is effective in reversing established disease compared to either monotherapy in both the NOD and rat insulin promotor-lymphocytic choriomeningitis virus glycoprotein (RIP-LCMV-GP) models of autoimmune diabetes. Enhanced efficacy is particularly evident in severely hyperglycemic mice, with return to normoglycemia remaining stable for the majority of mice even after therapy is withdrawn. Importantly, increased beta cell proliferation does not appear to be the predominant mechanism. In conclusion, combination therapy with anti-IL-21 and liraglutide is able to consistently reverse disease in mouse models of T1D. The observed effects rival the most effective experimental disease-modifying treatments tested in preclinical studies.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Diabetes Mellitus Tipo 1/terapia , Hiperglicemia/terapia , Imunoterapia/métodos , Células Secretoras de Insulina/imunologia , Interleucinas/imunologia , Liraglutida/uso terapêutico , Animais , Diabetes Mellitus Tipo 1/imunologia , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Humanos , Hiperglicemia/imunologia , Insulina/genética , Insulina/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos Transgênicos
9.
J Autoimmun ; 81: 68-73, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28325643

RESUMO

Interleukin-1ß (IL-1ß) is known to trigger beta cell dysfunction in vitro and could potentially play a role during the pathogenesis of type 1 diabetes and type 2 diabetes. However, several clinical trials attempting to block IL-1ß function have had minimal success. We therefore re-investigated local expression of IL-1ß in human diabetic and non-diabetic pancreata. We obtained pancreatic tissue sections from the Network for Pancreatic Organ Donors with Diabetes (nPOD) including non-diabetic (n = 9), non-diabetic auto-antibody positive (AAb+, n = 5), type 1 diabetes (n = 6), and type 2 diabetes (n = 6) donors. Islets were systematically investigated for the presence of IL-1ß mRNA by in situ hybridization and IL-1ß protein by indirect immunofluorescence. We found that intra-islet IL-1ß was produced at comparable level in both non-diabetic and diabetic donors. Interestingly, the main source for IL-1ß was alpha cells but not beta cells. Our findings call into question the role of IL-1ß in the diabetic pancreas as it has been proposed in previous literature. Additionally, our results regarding the localization of IL-1ß should lead to further investigation into the role of IL-1ß in the physiology of pancreatic alpha cells.


Assuntos
Células Secretoras de Glucagon/metabolismo , Interleucina-1beta/metabolismo , Pâncreas/citologia , Pâncreas/metabolismo , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Expressão Gênica , Humanos , Interleucina-1beta/genética , Pâncreas/patologia
10.
Diabetes ; 66(5): 1334-1345, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28137793

RESUMO

Type 1 diabetes is characterized by the loss of insulin production caused by ß-cell dysfunction and/or destruction. The hypothesis that ß-cell loss occurs early during the prediabetic phase has recently been challenged. Here we show, for the first time in situ, that in pancreas sections from autoantibody-positive (Ab+) donors, insulin area and ß-cell mass are maintained before disease onset and that production of proinsulin increases. This suggests that ß-cell destruction occurs more precipitously than previously assumed. Indeed, the pancreatic proinsulin-to-insulin area ratio was also increased in these donors with prediabetes. Using high-resolution confocal microscopy, we found a high accumulation of vesicles containing proinsulin in ß-cells from Ab+ donors, suggesting a defect in proinsulin conversion or an accumulation of immature vesicles caused by an increase in insulin demand and/or a dysfunction in vesicular trafficking. In addition, islets from Ab+ donors were larger and contained a higher number of ß-cells per islet. Our data indicate that ß-cell mass (and function) is maintained until shortly before diagnosis and declines rapidly at the time of clinical onset of disease. This suggests that secondary prevention before onset, when ß-cell mass is still intact, could be a successful therapeutic strategy.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Células Secretoras de Insulina/metabolismo , Pâncreas/metabolismo , Estado Pré-Diabético/metabolismo , Proinsulina/metabolismo , Adulto , Autoanticorpos , Estudos de Casos e Controles , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Feminino , Imunofluorescência , Humanos , Células Secretoras de Insulina/patologia , Masculino , Microscopia Confocal , Pessoa de Meia-Idade , Pâncreas/patologia , Estado Pré-Diabético/patologia , Vesículas Transportadoras/metabolismo , Vesículas Transportadoras/patologia , Adulto Jovem
11.
Diabetes Obes Metab ; 19(5): 705-712, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28094469

RESUMO

AIMS: Glucagon-like peptide-1 (GLP-1) is an incretin hormone which stimulates insulin release and inhibits glucagon secretion from the pancreas in a glucose-dependent manner. Incretin-based therapies, consisting of GLP-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, are used for the treatment of type 2 diabetes (T2D). Immunohistochemical studies for GLP-1R expression have been hampered previously by the use of unspecific polyclonal antibodies. This study aimed to assess the expression levels of GLP-1R in a set of T2D donor samples obtained via nPOD. METHODS: This study used a new monoclonal antibody to assess GLP-1R expression in pancreatic tissue from 23 patients with T2D, including 7 with a DPP-4 inhibitor and 1 with a history of GLP-1R agonist treatment. A software-based automated image analysis algorithm was used for quantitating intensities and area fractions of GLP-1R positive compartments. RESULTS: The highest intensity GLP-1R immunostaining was seen in beta-cells in islets (average signal intensity, 76.1 [±8.1]). GLP-1R/insulin double-labelled single cells or small clusters of cells were also frequently located within or in close vicinity of ductal epithelium in all samples and with the same GLP-1R immunostaining intensity as found in beta-cells in islets. In the exocrine pancreas a large proportion of acinar cells expressed GLP-1R with a 3-fold lower intensity of immunoreactivity as compared to beta-cells (average signal intensity 25.5 [±3,3]). Our studies did not unequivocally demonstrate GLP-1R immunoreactivity on normal-appearing ductal epithelium. Pancreatic intraepithelial neoplasia (PanINs; a form of non-invasive pancreatic ductular neoplasia) was seen in most samples, and a minority of these expressed low levels of GLP-1R. CONCLUSION: These data confirm the ubiquity of early stage PanIN lesions in patients with T2D and do not support the hypothesis that incretin-based therapies are associated with progression towards the more advanced stage PanIN lesions.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Células Secretoras de Insulina/metabolismo , Pâncreas/metabolismo , Adolescente , Adulto , Idoso , Anticorpos Monoclonais , Especificidade de Anticorpos , Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Feminino , Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Hipoglicemiantes/uso terapêutico , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Incretinas/uso terapêutico , Insulina/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/patologia , Masculino , Pessoa de Meia-Idade , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Bancos de Tecidos , Adulto Jovem
13.
Autoimmun Rev ; 15(10): 964-9, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27491567

RESUMO

Type 1 diabetes (T1D) is an autoimmune disease characterized by the loss of pancreatic beta cells in the islets of Langerhans. Although genetic predisposition plays an important role in T1D development, studies of identical twins suggest that environmental factors such as viruses and other pathogens may be critical triggers either through direct cytolytic effect and gradual beta cell destruction, or by bystander activation of the immune system. In addition, viruses may circumvent the host immune response and have the capacity to establish chronic lifelong infections. The association of various viral infections with the induction of T1D has been extensively studied at the serological and epidemiological level. However, there is still little evidence from studies of human pancreas to confirm their presence or a causal role in disease pathogenesis. In this review, we identify possible suspects for viral triggers of disease and explain their potential roles in the "viral paradigm" of T1D.


Assuntos
Diabetes Mellitus Tipo 1/virologia , Viroses/complicações , Animais , Autoimunidade , Diabetes Mellitus Tipo 1/imunologia , Humanos , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/virologia , Viroses/imunologia
14.
Front Immunol ; 7: 313, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27574523

RESUMO

Cytotoxic T lymphocytes execute the killing of insulin-producing beta cells during onset of type 1 diabetes mellitus (T1D). The research community has come far in dissecting the major events in the development of this disease, but still the trigger and high-resolved information of the immunological events leading up to beta cell loss are missing. During the past decades, intravital imaging of immune responses has led to significant scientific breakthroughs in diverse models of disease, including T1D. Dynamic imaging of immune cells at the pancreatic islets during T1D onset has been made possible through the development of both advanced microscopes, and animal models that allow long-term immobilization of the pancreas. The use of these modalities has revealed a milling microenvironment at the pancreatic islets during disease onset with a plethora of active players. Clues to answering the remaining questions in this disease may lie in intravital imaging, including how key immune cells traffic to and from the pancreas, and how cells interact at this target tissue. This review highlights and discusses recent studies, models, and techniques focused to understand the immune responses during T1D onset through intravital imaging.

16.
Clin Immunol ; 161(1): 37-43, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26122172

RESUMO

The standard of care (SoC) for Type 1 diabetes (T1D) today is much the same as it was in the early 1920s, simply with more insulin options-fast-acting, slow-acting, injectable, and inhalable insulins. However, these well-tolerated treatments only manage the symptoms and complications, but do nothing to halt the underlying immune response. There is an unmet need for better treatment options for T1D that address all aspects of the disease. For decades, we have successfully treated T1D in preclinical animal models with immune-modifying therapies that have not demonstrated comparable efficacy in humans. The path to bringing such options to the clinic will depend on the implementation and standard inclusion of biomarkers of immune and therapeutic efficacy in T1D clinical trials, and dictate if we can create a new SoC that treats the underlying autoimmunity as well as the symptoms it causes.


Assuntos
Biomarcadores/análise , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/terapia , Imunoterapia , Animais , Autoanticorpos/análise , Autoanticorpos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Modelos Animais de Doenças , Humanos , Sensibilidade e Especificidade , Linfócitos T/imunologia , Linfócitos T/metabolismo
17.
J Histochem Cytochem ; 63(8): 626-36, 2015 08.
Artigo em Inglês | MEDLINE | ID: mdl-26216138

RESUMO

Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing beta cells are destroyed in the islets of Langerhans. One of its main pathological manifestations is the hyper-expression of Major Histocompatibility Complex I (MHC-I) by beta cells, which was first described over 3 decades ago yet its cause remains unknown. It might not only be a sign of beta cell dysfunction but could also render the cells susceptible to autoimmune destruction; for example, by islet-infiltrating CD8 T cells. In this report, we studied pancreas tissue from a 22-year-old non-diabetic male cadaveric organ donor who had been at high risk of developing T1D, in which autoantibodies against GAD and IA-2 were detected. Pancreas sections were analyzed for signs of inflammation. Multiple insulin-containing islets were identified, which hyper-expressed MHC-I. However, islet density and MHC-I expression exhibited a highly lobular and heterogeneous pattern even within the same section. In addition, many islets with high expression of MHC-I presented higher levels of CD8 T cell infiltration than normal islets. These results demonstrate the heterogeneity of human pathology that occurs early during the pre-diabetic, autoantibody positive phase, and should contribute to the understanding of human T1D.


Assuntos
Diabetes Mellitus Tipo 1/patologia , Pâncreas/patologia , Estado Pré-Diabético/patologia , Autoanticorpos/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Antígenos de Histocompatibilidade Classe I/biossíntese , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Masculino , Pâncreas/metabolismo , Estado Pré-Diabético/metabolismo , Adulto Jovem
19.
Front Immunol ; 6: 651, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26793191

RESUMO

Regulatory T cells (Tregs) play an important role in preventing effector T-cell (Teff) targeting of self-antigens that can lead to tissue destruction in autoimmune settings, including type 1 diabetes (T1D). Autoimmunity is caused in part by an imbalance between Teff and Tregs. Early attempts to treat with immunosuppressive agents have led to serious side effects, thus requiring a more targeted approach. Low-dose IL-2 (LD IL-2) can provide immunoregulation with few side effects by preferentially acting on Tregs to drive tolerance. The concept of LD IL-2 as a therapeutic approach is supported by data in mouse models where autoimmunity is cured and further strengthened by success in human clinical studies in hepatitis C virus-induced vasculitis, chronic graft-versus-host disease, and Alopecia areata. Treatment will require identification of a safe therapeutic window, which is a difficult task given that patients are reported to have deficient or defective IL-2 production or signaling and have experienced mild activation of NK cells and eosinophils with LD IL-2 therapy. In T1D, an LD IL-2 clinical trial concluded that Tregs can be safely expanded in humans; however, the study was not designed to address efficacy. Antigen-specific therapies have also aimed at regulation of the autoimmune response but have been filled with disappointment despite an extensive list of diverse islet antigens tested in humans. This approach could be enhanced through the addition of LD IL-2 to the antigenic treatment regimen to improve the frequency and function of antigen-specific Tregs, without global immunosuppression. Here, we will discuss the use of LD IL-2 and islet antigen to enhance antigen-specific Tregs in T1D and focus on what is known about their immunological impact, their safety, and potential efficacy, and need for better methods to identify therapeutic effectiveness.

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