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1.
Clin Immunol ; 244: 109118, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36084852

RESUMO

To enable accurate, high-throughput and longer-term studies of the immunopathogenesis of type 1 diabetes (T1D), we established three in-vitro islet-immune injury models by culturing spheroids derived from primary human islets with proinflammatory cytokines, activated peripheral blood mononuclear cells or HLA-A2-restricted preproinsulin-specific cytotoxic T lymphocytes. In all models, ß-cell function declined as manifested by increased basal and decreased glucose-stimulated insulin release (GSIS), and decreased intracellular insulin content. Additional hallmarks of T1D progression such as loss of the first-phase insulin response (FFIR), increased proinsulin-to-insulin ratios, HLA-class I expression, and inflammatory cytokine release were also observed. Using these models, we show that liraglutide, a glucagon-like peptide 1 receptor agonist, prevented loss of GSIS under T1D-relevant stress, by preserving the FFIR and decreasing immune cell infiltration and cytokine secretion. Our results corroborate that liraglutide mediates an anti-inflammatory effect that aids in protecting ß-cells from the immune-mediated attack that leads to T1D.


Assuntos
Diabetes Mellitus Tipo 1 , Células Secretoras de Insulina , Ilhotas Pancreáticas , Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Glucose/metabolismo , Antígeno HLA-A2 , Humanos , Insulina , Células Secretoras de Insulina/metabolismo , Leucócitos Mononucleares/metabolismo , Liraglutida/metabolismo , Liraglutida/farmacologia , Proinsulina/metabolismo
2.
J Autoimmun ; 119: 102628, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33706238

RESUMO

Human leukocyte antigens of class-I (HLA-I) molecules are hyper-expressed in insulin-containing islets (ICI) of type 1 diabetic (T1D) donors. This study investigated the HLA-I expression in autoantibody positive (AAB+) donors and defined its intra-islet and intracellular localization as well as proximity to infiltrating CD8 T cells with high-resolution confocal microscopy. We found HLA-I hyper-expression had already occurred prior to clinical diagnosis of T1D in islets of AAB+ donors. Interestingly, throughout all stages of disease, HLA-I was mostly expressed by alpha cells. Hyper-expression in AAB+ and T1D donors was associated with intra-cellular accumulation in the Golgi. Proximity analysis showed a moderate but significant correlation between HLA-I and infiltrating CD8 T cells only in ICI of T1D donors, but not in AAB+ donors. These observations not only demonstrate a very early, islet-intrinsic immune-independent increase of HLA-I during diabetes pathogenesis, but also point towards a role for alpha cells in T1D.


Assuntos
Expressão Gênica , Células Secretoras de Glucagon/metabolismo , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/metabolismo , Estado Pré-Diabético/etiologia , Estado Pré-Diabético/imunologia , Autoanticorpos/imunologia , Autoantígenos/imunologia , Autoimunidade , Biomarcadores , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/metabolismo , Suscetibilidade a Doenças/imunologia , Imunofluorescência , Humanos , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Transporte Proteico , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
3.
Immunity ; 36(6): 1060-72, 2012 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-22579473

RESUMO

It remains unclear how interleukin-21 receptor (IL-21R) contributes to type 1 diabetes. Here we have shown that dendritic cells (DCs) in the pancreas required IL-21R not for antigen uptake, but to acquire the chemokine receptor CCR7 and migrate into the draining lymph node. Consequently, less antigen, major histocompatibility complex (MHC) class II, and CD86 was provided to autoreactive effector cells in Il21r(-/-) mice, impairing CD4(+) T cell activation, CD40:CD40L interactions, and pancreatic infiltration by autoreactive T cells. CD40 crosslinking restored defective CD4(+) cell expansion and CD4 independently expanded autoreactive CD8(+) cells, but CD8(+) cells still required CD4(+) cells to reach the pancreas and induce diabetes. Diabetes induction by transferred T cells required IL-21R-sufficient host antigen-presenting cells. Transferring IL-21R-sufficient DCs broke diabetes resistance in Il21r(-/-) mice. We conclude that IL-21R controls both antigen transport by DCs and the crucial beacon function of CD4(+) cells for autoreactive CD8(+) cells to reach the islets.


Assuntos
Autoimunidade/imunologia , Diabetes Mellitus Tipo 1/imunologia , Subunidade alfa de Receptor de Interleucina-21/fisiologia , Ilhotas Pancreáticas/imunologia , Subpopulações de Linfócitos T/imunologia , Transferência Adotiva , Animais , Apresentação de Antígeno , Linfócitos T CD4-Positivos/imunologia , Antígenos CD40/imunologia , Ligante de CD40/imunologia , Linfócitos T CD8-Positivos/imunologia , Quimiotaxia de Leucócito , Diabetes Mellitus Tipo 1/patologia , Modelos Animais de Doenças , Resistência à Doença , Subunidade alfa de Receptor de Interleucina-21/deficiência , Subunidade alfa de Receptor de Interleucina-21/genética , Linfonodos/imunologia , Linfonodos/patologia , Ativação Linfocitária , Cooperação Linfocítica , Vírus da Coriomeningite Linfocítica , Camundongos , Camundongos Endogâmicos NOD , Receptores CCR7/metabolismo , Organismos Livres de Patógenos Específicos , Baço/imunologia , Subpopulações de Linfócitos T/transplante
4.
J Autoimmun ; 107: 102378, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31818546

RESUMO

Human herpesvirus-6 (HHV-6) is a ubiquitous pathogen associated with nervous and endocrine autoimmune disorders. The aim of this study was to investigate the presence of HHV-6 in pancreatic tissue sections from non-diabetic, auto-antibody positive (AAB+), and donors with type 1 diabetes (T1D) and explore whether there is any association between HHV-6 and MHC class I hyperexpression and CD8 T cell infiltration. HHV-6 DNA was detected by PCR and its protein was examined by indirect immunofluorescence assay followed by imaging using high-resolution confocal microscopy. Viral DNA (U67) was found in most pancreata of non-diabetic (3 out of 4), AAB+ (3 out of 5) and T1D donors (6 out of 7). Interestingly, HHV-6 glycoprotein B (gB) was more expressed in islets and exocrine pancreas of donors with T1D. However, gB expression was not directly associated with other pathologies. Out of 20 islets with high gB expression, only 3 islets (15%) showed MHC class I hyperexpression. Furthermore, no correlation was found between gB expression and CD8 T cell infiltration on a per-islet basis in any of the groups. Our observations indicate that HHV-6 DNA and protein are present in the pancreas of non-diabetic subjects but gB expression is higher in the pancreas of donors with T1D. The possible role of HHV-6 as a contributory factor for T1D should therefore be further investigated.


Assuntos
Diabetes Mellitus Tipo 1/etiologia , Suscetibilidade a Doenças , Herpesvirus Humano 6 , Pâncreas/virologia , Infecções por Roseolovirus/complicações , Autoimunidade , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/metabolismo , Expressão Gênica , Herpesvirus Humano 6/genética , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/virologia , Pâncreas/imunologia , Pâncreas/metabolismo , Infecções por Roseolovirus/virologia
6.
Physiol Rev ; 91(1): 79-118, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21248163

RESUMO

Type 1 diabetes (T1D) is a chronic autoimmune disease in which destruction or damaging of the beta-cells in the islets of Langerhans results in insulin deficiency and hyperglycemia. We only know for sure that autoimmunity is the predominant effector mechanism of T1D, but may not be its primary cause. T1D precipitates in genetically susceptible individuals, very likely as a result of an environmental trigger. Current genetic data point towards the following genes as susceptibility genes: HLA, insulin, PTPN22, IL2Ra, and CTLA4. Epidemiological and other studies suggest a triggering role for enteroviruses, while other microorganisms might provide protection. Efficacious prevention of T1D will require detection of the earliest events in the process. So far, autoantibodies are most widely used as serum biomarker, but T-cell readouts and metabolome studies might strengthen and bring forward diagnosis. Current preventive clinical trials mostly focus on environmental triggers. Therapeutic trials test the efficacy of antigen-specific and antigen-nonspecific immune interventions, but also include restoration of the affected beta-cell mass by islet transplantation, neogenesis and regeneration, and combinations thereof. In this comprehensive review, we explain the genetic, environmental, and immunological data underlying the prevention and intervention strategies to constrain T1D.


Assuntos
Diabetes Mellitus Tipo 1/genética , Animais , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/terapia , Predisposição Genética para Doença , Humanos , Estado Pré-Diabético/diagnóstico , Prevenção Primária
7.
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.


Assuntos
Diabetes Mellitus Experimental/microbiologia , Diabetes Mellitus Tipo 1/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Insulina Regular de Porco/administração & dosagem , Administração Oral , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/patologia , Disbiose/imunologia , Disbiose/patologia , Fezes/microbiologia , Feminino , Insulina Regular de Porco/efeitos adversos , Camundongos , Camundongos Endogâmicos NOD , Suínos
8.
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
9.
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
10.
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
11.
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
12.
Nat Rev Immunol ; 3(3): 223-32, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12658270

RESUMO

The ultimate goal of any treatment for autoimmune diseases is antigen- and/or site-specific suppression of pathology. Autoaggressive lymphocytes need to be eliminated or controlled to prevent tissue damage and halt the progression of clinical disease. Strong evidence is emerging that the induction of regulatory T (T(Reg)) cells by autoantigens can suppress disease, even if the primary, initiating autoantigens are unknown and if inflammation is progressive. An advantage of these autoreactive T(Reg) cells is their ability to act as bystander suppressors and dampen inflammation in a site-specific manner in response to cognate antigen expressed locally by affected tissues. In this review, we consider the nature and function of such antigen-specific T(Reg) cells, and strategies for their therapeutic induction are discussed.


Assuntos
Autoantígenos/imunologia , Autoimunidade/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Animais , Apresentação de Antígeno , Autoantígenos/administração & dosagem , Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Humanos
13.
Diabetologia ; 57(10): 2009-18, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25073445

RESUMO

In type 1 diabetes, as a result of as yet unknown triggering events, auto-aggressive CD8(+) T cells, together with a significant number of other inflammatory cells, including CD8(+) T lymphocytes with unknown specificity, infiltrate the pancreas, leading to insulitis and destruction of the insulin-producing beta cells. Type 1 diabetes is a multifactorial disease caused by an interactive combination of genetic and environmental factors. Viruses are major environmental candidates with known potential effects on specific key points in the pathogenesis of type 1 diabetes and recent findings seem to confirm this presumption. However, we still lack well-grounded mechanistic explanations for how exactly viruses may influence type 1 diabetes aetiology. In this review we provide a summary of experimentally defined viral mechanisms potentially involved in the ontology of type 1 diabetes and discuss some novel hypotheses of how viruses may affect the initiation and natural history of the disease.


Assuntos
Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/virologia , Autoimunidade/imunologia , Linfócitos T CD8-Positivos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Humanos , Viroses/complicações , Viroses/imunologia
14.
PLoS Pathog ; 8(9): e1002913, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22969431

RESUMO

During acute viral infections, clearance of the pathogen is followed by the contraction of the anti-viral T cell compartment. In contrast, T cell responses need to be maintained over a longer period of time during chronic viral infections in order to control viral replication and to avoid viral spreading. Much is known about inhibitory signals such as through PD-1 that limit T cell activity during chronic viral infection, but little is known about the stimulatory signals that allow maintenance of anti-viral T cells. Here, we show that the co-stimulatory molecule OX40 (CD134) is critically required in the context of persistent LCMV clone 13 infection. Anti-viral T cells express high levels of OX40 in the presence of their cognate antigen and T cells lacking the OX40 receptor fail to accumulate sufficiently. Moreover, the emergence of T cell dependent germinal center responses and LCMV-specific antibodies are severely impaired. Consequently, OX40-deficient mice fail to control LCMV clone 13 infection over time, highlighting the importance of this signaling pathway during persistent viral infection.


Assuntos
Imunidade Adaptativa/genética , Receptores OX40/fisiologia , Viroses/imunologia , Viroses/prevenção & controle , Doença Aguda , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Chlorocebus aethiops , Centro Germinativo/metabolismo , Centro Germinativo/fisiologia , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Coriomeningite Linfocítica/genética , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/prevenção & controle , Vírus da Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores OX40/genética , Receptores OX40/metabolismo , Células Vero , Viroses/genética , Latência Viral/imunologia , Latência Viral/fisiologia
15.
J Autoimmun ; 55: 24-32, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24582317

RESUMO

Inflammatory mechanisms play a key role in the pathogenesis of type 1 and type 2 diabetes. IL6, a pleiotropic cytokine with impact on immune and non-immune cell types, has been proposed to be involved in the events causing both forms of diabetes and to play a key role in experimental insulin-dependent diabetes development. The aim of this study was to investigate how beta-cell specific overexpression of IL-6 influences diabetes development. We developed two lines of rat insulin promoter (RIP)-lymphocytic choriomeningitis virus (LCMV) mice that also co-express IL6 in their beta-cells. Expression of the viral nucleoprotein (NP), which has a predominantly intracellular localization, together with IL6 led to hyperglycemia, which was associated with a loss of GLUT-2 expression in the pancreatic beta-cells and infiltration of CD11b(+) cells, but not T cells, in the pancreas. In contrast, overexpression of the LCMV glycoprotein (GP), which can localize to the surface, with IL-6 did not lead to spontaneous diabetes, but accelerated virus-induced diabetes by increasing autoantigen-specific CD8(+) T cell responses and reducing the regulatory T cell fraction, leading to increased pancreatic infiltration by CD4(+) and CD8(+) T cells as well as CD11b(+) and CD11c(+) cells. The production of IL-6 in beta-cells acts prodiabetic, underscoring the potential benefit of targeting IL6 in diabetes.


Assuntos
Diabetes Mellitus Experimental/imunologia , Células Secretoras de Insulina/imunologia , Interleucina-6/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Nucleoproteínas/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Transportador de Glucose Tipo 2/genética , Transportador de Glucose Tipo 2/imunologia , Hiperglicemia/imunologia , Células Secretoras de Insulina/patologia , Interleucina-6/genética , Vírus da Coriomeningite Linfocítica/genética , Camundongos , Camundongos Transgênicos , Nucleoproteínas/genética , Ratos
17.
Clin Immunol ; 149(3): 345-55, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23490422

RESUMO

Type 1 diabetes (T1D) results from an aberrant immunological response against the insulin-producing beta cells in the islets of the pancreas. The ideal therapy would restore immune balance in a safe and lasting fashion, stopping the process of beta cell decay. The efficacy of immune suppressive agents such as cyclosporin underscores the notion that T1D can in principle be prevented, albeit at an unacceptable long-term safety risk. Immune modulatory drugs such as monoclonal anti-CD3 antibody, on the other hand, have recently had rather disappointing results in phase 3 trials, possibly due to inadequate dosing or choice of inappropriate endpoints. Therefore, it is argued that striking the right balance between safety and efficacy, together with careful trial design, will be paramount in preventing T1D. Here we outline the concept of antigen-specific tolerization as a strategy to safely induce long-term protection against T1D, focusing on available clinical trial data, key knowledge gaps and potential future directions.


Assuntos
Autoantígenos/imunologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Células Secretoras de Insulina/efeitos dos fármacos , Anticorpos Monoclonais/uso terapêutico , Autoantígenos/metabolismo , Complexo CD3/imunologia , Complexo CD3/metabolismo , Chaperonina 60/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/prevenção & controle , Glutamato Descarboxilase/uso terapêutico , Humanos , Tolerância Imunológica , Insulina/imunologia , Insulina/metabolismo , Insulina/uso terapêutico , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/patologia , Fragmentos de Peptídeos/uso terapêutico , Precursores de Proteínas/uso terapêutico , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/patologia
18.
J Autoimmun ; 40: 66-73, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22944096

RESUMO

It is thought that viral infections might jeopardize regulatory T cell therapy in type 1 diabetes. Viral infections can lead to surface expression of ligands for the activating NKG2D receptor, such as retinoic acid early transcript 1 (Rae-1), whose expression on beta-cells recruits NKG2D(+) autoreactive CD8(+) T cells. Both in men and mice, autoreactive cytotoxic T cells express NKG2D. We showed that NKG2D expression increased on CD4(+) and CD8(+) T cells during virus-induced diabetes development in the rat insulin promotor (RIP) Lymphocytic Choriomeningitis Virus (LCMV) model. Combination treatment with anti-NKG2D and antigen-specific regulatory T cells (Treg), at doses inefficacious in mono-treatment, synergized to prevent diabetes in 75% of the virus-infected RIP-LCMV mice. Nevertheless, NKG2D blockade alone failed to reverse recent-onset diabetes in non-obese diabetic (NOD) mice, despite downregulation of NKG2D on NK cells in the blood and CD8(+) T cells in the spleen and pancreatic lymph nodes. Our data suggest that blocking the interaction of NKG2D with it ligands is insufficient to protect against diabetes when a strong inflammatory process actively drives NKG2D upregulation, but should be considered to help maintaining Treg functionality during ongoing pancreatic inflammation.


Assuntos
Diabetes Mellitus Tipo 1/prevenção & controle , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Anticorpos/imunologia , Linfócitos T CD8-Positivos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/virologia , Células Matadoras Naturais/imunologia , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos NOD , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Proteínas Associadas à Matriz Nuclear/biossíntese , Proteínas de Transporte Nucleocitoplasmático/biossíntese , Pâncreas/imunologia , Pâncreas/virologia , Baço/imunologia
19.
J Immunol ; 187(6): 2915-22, 2011 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-21832162

RESUMO

Recent studies have shown that IL-17 can contribute beneficially to pathogen defense but also that excessive IL-17 levels are associated with chronic inflammation and autoimmune disorders. To date, the role of IL-17 in viral infections and type 1 diabetes is ambiguous. In this study, we used IL-17A enhanced green fluorescent protein bicistronic reporter mouse strains to analyze in situ production of IL-17A. Upon Klebsiella pneumoniae bacterial infection, CD4(+) and γδ T cells produce IL-17A. In contrast, CD4(+) or CD8(+) T cells do not produce IL-17A in response to acute or protracted viral infection with lymphocytic choriomeningitis virus or during autoimmune diabetes development in the CD8-driven lymphocytic choriomeningitis virus-induced model of type 1 diabetes. We conclude that viral elimination and type 1 diabetes can occur in the absence of detectable IL-17A production, suggesting IL-17A is not essential in these settings.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Interleucina-17/imunologia , Viroses/imunologia , Animais , Linfócitos T CD4-Positivos , Separação Celular , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Técnicas de Introdução de Genes , Genes Reporter , Proteínas de Fluorescência Verde/genética , Vírus da Coriomeningite Linfocítica/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
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