scholarly journals Immature Dendritic Cell Therapy Confers Durable Immune Modulation in an Antigen-Dependent and Antigen-Independent Manner in Nonobese Diabetic Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Jeannette Lo ◽  
Chang-Qing Xia ◽  
Ruihua Peng ◽  
Michael J. Clare-Salzler
Keyword(s):  
Dendritic Cell ◽  
Neutralizing Antibodies ◽  
Immune Modulation ◽  
T Regulatory Cells ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Independent Manner ◽  
Nonobese Diabetic Mice ◽  
Dendritic Cell Therapy

Dendritic cell (DC) immunotherapy has been effective for prevention of type 1 diabetes (T1D) in NOD mice but fails to protect if initiated after active autoimmunity. As autoreactivity expands inter- and intramolecularly during disease progression, we investigated whether DCs unpulsed or pulsed with β cell antigenic dominant determinants (DD), subdominant determinants (SD), and ignored determinants (ID) could prevent T1D in mice with advanced insulitis. We found that diabetes was significantly delayed by DC therapy. Of interest, DCs pulsed with SD or ID appeared to provide better protection. T lymphocytes from DC-treated mice acquired spontaneous proliferating capability during in vitro culture, which could be largely eliminated by IL-2 neutralizing antibodies. This trend maintained even 29 weeks after discontinuing DC therapy and appeared antigen-independent. Furthermore, CD4+Foxp3+ T regulatory cells (Tregs) from DC-treated mice proliferated more actively in vitro compared to the controls, and Tregs from DC-treated mice showed significantly enhanced immunosuppressive activities in contrast to those from the controls. Our study demonstrates that DC therapy leads to long-lasting immunomodulatory effects in an antigen-dependent and antigen-independent manner and provides evidence for peptide-based intervention during a clinically relevant window to guide DC-based immunotherapy for autoimmune diabetes.

InsB9-23 Gene Transfer To Hepatocytes-Based Combined Therapy Abrogates Recurrence of Type-1 Diabetes After Islet Transplantation

2020 ◽  
Author(s):  
Ada Admin ◽  
Fabio Russo ◽  
Antonio Citro ◽  
Giorgia Squeri ◽  
Francesca Sanvito ◽  
...  
Keyword(s):  
T Regulatory Cells ◽  
Lentiviral Vector ◽  
Autoimmune Diabetes ◽  
Therapeutic Option ◽  
Combined Therapy ◽  
Cell Mass ◽  
Nod Mice ◽  
Β Cell ◽  
Suboptimal Dose ◽  
Islets Transplantation

The induction of antigen (Ag)-specific tolerance represents a therapeutic option for autoimmune diabetes. We demonstrated that administration of lentiviral vector enabling expression of insulinB9-23 (LV.InsB) in hepatocytes, arrests β cell destruction in pre-diabetic NOD mice, by generating InsB9-23-specific FoxP3+T regulatory cells (Tregs). LV.InsB in combination with a suboptimal dose of anti-CD3 mAb (combined therapy, 1X5µg CT5) reverts diabetes and prevents recurrence of autoimmunity following islets transplantation in ~50% of NOD mice. We investigated whether CT optimization could lead to abrogation of recurrence of autoimmunity. Therefore, allo-islets were transplanted after optimized CT tolerogenic conditioning (1X25µg CT25). Diabetic NOD mice conditioned with CT25 when glycaemia was <500mg/dL, remained normoglycaemic for 100 days after allo-islets transplantation, displayed reduced insulitis, but independently from the graft. Accordingly, cured mice showed T cell unresponsiveness to InsB9-23 stimulation and increased Tregs frequency in islets infiltration and pancreatic LN. Additional studies revealed a complex mechanism of Ag-specific immune regulation driven by CT25, in which both Tregs and PDL1 co-stimulation cooperate to control diabetogenic cells, while transplanted islets play a crucial role, although transient, recruiting diabetogenic cells. Therefore, CT25 before allo-islets transplantation represents an Ag-specific immunotherapy to resolve autoimmune diabetes in the presence of residual endogenous β cell mass.

Pro-apoptotic DNA vaccination ameliorates new onset of autoimmune diabetes in NOD mice and induces foxp3+ regulatory T cells in vitro

Vaccine ◽  
2006 ◽  
Vol 24 (23) ◽  
pp. 5036-5046 ◽  
Author(s):  
Alice Li ◽  
Okechukwu Ojogho ◽  
Edson Franco ◽  
Pedro Baron ◽  
Yuichi Iwaki ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Dna Vaccination ◽  
New Onset

scholarly journals Dendritic cell–expanded, islet-specific CD4+ CD25+ CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice

2007 ◽  
Vol 204 (1) ◽  
pp. 191-201 ◽  
Author(s):  
Kristin V. Tarbell ◽  
Lucine Petit ◽  
Xiaopan Zuo ◽  
Priscilla Toy ◽  
Xunrong Luo ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cell ◽  
Regulatory T Cells ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Cell Receptor ◽  
Suppressor T Cells ◽  
Nonobese Diabetic ◽  
Glucose Challenge ◽  
Infiltrating Lymphocytes

Most treatments that prevent autoimmune diabetes in nonobese diabetic (NOD) mice require intervention at early pathogenic stages, when insulitis is first developing. We tested whether dendritic cell (DC)–expanded, islet antigen–specific CD4+ CD25+ suppressor T cells could treat diabetes at later stages of disease, when most of the insulin-producing islet β cells had been destroyed by infiltrating lymphocytes. CD4+ CD25+ CD62L+ regulatory T cells (T reg cells) from BDC2.5 T cell receptor transgenic mice were expanded with antigen-pulsed DCs and IL-2, and were then injected into NOD mice. A single dose of as few as 5 × 104 of these islet-specific T reg cells blocked diabetes development in prediabetic 13-wk-old NOD mice. The T reg cells also induced long-lasting reversal of hyperglycemia in 50% of mice in which overt diabetes had developed. Successfully treated diabetic mice had similar responses to glucose challenge compared with nondiabetic NOD mice. The successfully treated mice retained diabetogenic T cells, but also had substantially increased Foxp3+ cells in draining pancreatic lymph nodes. However, these Foxp3+ cells were derived from the recipient mice and not the injected T reg cells, suggesting a role for endogenous T reg cells in maintaining tolerance after treatment. Therefore, inoculation of DC-expanded, antigen-specific suppressor T cells has considerable efficacy in ameliorating ongoing diabetes in NOD mice.

scholarly journals Immunogenicity of personalized dendritic-cell therapy in HIV-1 infected individuals under suppressive antiretroviral treatment: interim analysis from a phase II clinical trial

2022 ◽  
Vol 19 (1) ◽  
Author(s):  
Marcella Vassão de Almeida Baptista ◽  
Laís Teodoro da Silva ◽  
Sadia Samer ◽  
Telma Miyuki Oshiro ◽  
Iart Luca Shytaj ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
Cell Therapy ◽  
Antiretroviral Treatment ◽  
Gm Csf ◽  
Ifn Γ ◽  
Dendritic Cell Therapy ◽  
Hiv 1

Abstract Background We developed a personalized Monocyte-Derived Dendritic-cell Therapy (MDDCT) for HIV-infected individuals on suppressive antiretroviral treatment and evaluated HIV-specific T-cell responses. Methods PBMCs were obtained from 10 HIV+ individuals enrolled in trial NCT02961829. Monocytes were differentiated into DCs using IFN-α and GM-CSF. After sequencing each patient’s HIV-1 Gag and determining HLA profiles, autologous Gag peptides were selected based on the predicted individual immunogenicity and used to pulse MDDCs. Three doses of the MDDCT were administered every 15 days. To assess immunogenicity, patients’ cells were stimulated in vitro with autologous peptides, and intracellular IL-2, TNF, and interferon-gamma (IFN-γ) production were measured in CD4+ and CD8+ T-cells. Results The protocol of ex-vivo treatment with IFN-α and GM-CSF was able to induce maturation of MDDCs, as well as to preserve their viability for reinfusion. MDDCT administration was associated with increased expression of IL-2 in CD4+ and CD8+ T-cells at 15 and/or 30 days after the first MDDCT administration. Moreover, intracellular TNF and IFN-γ expression was significantly increased in CD4+ T-cells. The number of candidates that increased in vitro the cytokine levels in CD4+ and CD8+ T cells upon stimulation with Gag peptides from baseline to day 15 and from baseline to day 30 and day 120 after MDDCT was significant as compared to Gag unstimulated response. This was accompanied by an increasing trend in the frequency of polyfunctional T-cells over time, which was visible when considering both cells expressing two and three out of the three cytokines examined. Conclusions MDDC had a mature profile, and this MDDCT promoted in-vitro T-cell immune responses in HIV-infected patients undergoing long-term suppressive antiretroviral treatment. Trial registration NCT02961829: (Multi Interventional Study Exploring HIV-1 Residual Replication: a Step Towards HIV-1 Eradication and Sterilizing Cure, https://www.clinicaltrials.gov/ct2/show/NCT02961829, posted November 11th, 2016)

scholarly journals Toll-like receptor 4 inhibition prevents autoimmune diabetes in NOD mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Mohamed Alibashe-Ahmed ◽  
Estelle Brioudes ◽  
Walter Reith ◽  
Domenico Bosco ◽  
Thierry Berney
Keyword(s):  
T Lymphocyte ◽  
Autoimmune Diabetes ◽  
Lymphocyte Activation ◽  
Nod Mice ◽  
Diabetes Incidence ◽  
Preventive Strategy ◽  
Tlr4 Signaling ◽  
T Lymphocyte Activation ◽  
And Control

AbstractTLR4 is a transmembrane receptor of the innate immune system that recognizes LPS from gram-negative bacteria. Its stimulation induces pro-inflammatory responses and modulates adaptive immunity. Our aim is to determine the role of TLR4 in the activation and proliferation of T lymphocytes in the onset of autoimmune diabetes, using the non-obese diabetic (NOD) mouse model. Antigen-specific activation and proliferation of diabetogenic T cells were assessed in vitro by Carboxyfluorescein succinimidyl ester (CFSE) dilution, in presence of vehicle or CLI-095, a cyclohexene derivative that inhibits TLR4 signaling. NOD mice were treated with vehicle or CLI-095 and sacrificed either before or after the onset of autoimmune diabetes. T lymphocyte activation and proliferation were evaluated in treated and control mice. Insulitis was analyzed by histology and diabetes incidence was determined in treated and control mice. Our results demonstrate that TLR4 blockade decreases CD4+ T lymphocyte activation and auto-antigen-specific proliferation both in vitro and in vivo, decreases the infiltrative insulitis and finally prevents the onset of spontaneous diabetes. Taken together, our data demonstrate that TLR4 signaling contributes to the development and maintenance of autoimmune diabetes. The immunomodulatory effect of CLI-095 could be part of a preventive strategy targeting patients at risk for type 1 diabetes.

Su.17. Pro-Apoptotic Dna Vaccination Ameliorates New Onset of Autoimmune Diabetes in Nod Mice and Induces Foxp3 Regulatory T-Cells In Vitro

2006 ◽  
Vol 119 ◽  
pp. S165
Author(s):  
Alice Li ◽  
Okechukwu Ojogho ◽  
Edson Franco ◽  
Pedro Baron ◽  
Yuichi Iwaki ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Dna Vaccination ◽  
New Onset

scholarly journals Androgen treatment prevents diabetes in nonobese diabetic mice.

1992 ◽  
Vol 175 (5) ◽  
pp. 1409-1412 ◽  
Author(s):  
H S Fox
Keyword(s):  
Immune Cells ◽  
Autoimmune Diabetes ◽  
Disease Model ◽  
Disease Onset ◽  
Nod Mice ◽  
Model System ◽  
Androgen Treatment ◽  
Nonobese Diabetic ◽  
Islet Inflammation ◽  
Nonobese Diabetic Mice

The nonobese diabetic (NOD) mouse strain provides a model system for human autoimmune diabetes. This disease model is extensively used not only to examine the etiology and pathogenesis of diabetes, but also as a means to evaluate therapies. In NOD mice, the disease progresses from insulitis to islet destruction and clinical diabetes in a high percentage of female mice. In this study, androgen therapy, begun after the onset of insulitis, was found to prevent islet destruction and diabetes without eliminating the islet inflammation in female NOD mice. However, diabetes can be adoptively transferred into such hormone-treated recipients. The prevention of disease onset by androgen is likely due to the hormonal alteration of the development or function of the immune cells necessary for islet destruction.

scholarly journals Chromogranin A Deficiency Confers Protection from Autoimmune Diabetes Via Multiple Mechanisms

2021 ◽  
Author(s):  
Virginia M Stone ◽  
Marta Butrym ◽  
Minna M Hankaniemi ◽  
Amir-Babak Sioofy-Khojine ◽  
Vesa P Hytönen ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Disease Progression ◽  
Neutralizing Antibodies ◽  
Autoimmune Diabetes ◽  
Disease Model ◽  
Disease Onset ◽  
Nod Mice ◽  
Disease Etiology ◽  
Islet Inflammation

Enteroviruses, including the Coxsackievirus Bs (CVB), have been implicated as causal agents in human type 1 diabetes. Immunization of at-risk individuals with a CVB vaccine provides an attractive strategy for elucidating the role of CVBs in the disease etiology. Previously we have shown that an inactivated whole-virus vaccine covering all CVB serotypes (CVB1-6) is safe to administer and highly immunogenic in preclinical models, including non-human primates. Before initiating clinical trials with this type of vaccine it was also important to address whether a) the vaccine itself induces adverse immune reactions including accelerating diabetes onset in a diabetes prone host and b) the vaccine can prevent CVB induced diabetes in a well-established disease model. Here we present results from studies in which female NOD mice were left untreated, mock-vaccinated or vaccinated with CVB1-6 vaccine and monitored for insulitis occurrence or diabetes development. We demonstrate that vaccination induces virus neutralizing antibodies without altering insulitis scores or the onset of diabetes. We also show that NOD mice vaccinated with a CVB1 vaccine are protected from CVB-induced accelerated disease onset. Taken together, these studies show that CVB vaccines do not alter islet inflammation or accelerate disease progression in an animal model that spontaneously develops autoimmune type 1 diabetes. However, they can prevent CVB-mediated disease progression in the same model. <b></b>

scholarly journals Production of interleukin 10 by islet cells accelerates immune-mediated destruction of beta cells in nonobese diabetic mice.

1994 ◽  
Vol 179 (4) ◽  
pp. 1379-1384 ◽  
Author(s):  
L Wogensen ◽  
M S Lee ◽  
N Sarvetnick
Keyword(s):  
Islet Cells ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Insulin Dependent Diabetes Mellitus ◽  
Interleukin 10 ◽  
Diabetic Mouse ◽  
Dependent Diabetes Mellitus ◽  
Beta Cell Destruction ◽  
Nonobese Diabetic ◽  
Nonobese Diabetic Mice

The T helper type 2 (Th2) cell product interleukin 10 (IL-10) inhibits the proliferation and function of Th1 lymphocytes and macrophages (M phi). The nonobese diabetic mouse strain (NOD/Shi) develops a M phi and T cell-dependent autoimmune diabetes that closely resembles human insulin-dependent diabetes mellitus (IDDM). The objective of the present study was to explore the consequences of localized production of IL-10 on diabetes development in NOD/Shi mice. Surprisingly, local production of IL-10 accelerated the onset and increased the prevalence of diabetes, since diabetes developed at 5-10 wk of age in 92% of IL-10 positive I-A beta g7/g7, I-E- mice in first (N2) and second (N3) generation backcrosses between IL-10 transgenic BALB/c mice and (NOD/Shi) mice. None of the IL-10 negative major histocompatibility complex-identical littermates were diabetic at this age. Furthermore, diabetes developed in 33% of I-A beta g7/d, I-E+ N3 mice in the presence of IL-10 before the mice were 10 wk old. Our findings support the notion that IL-10 should not simply be regarded as an immunoinhibitory cytokine, since it possesses powerful, immunostimulatory properties as well. Furthermore, our observations suggest that beta cell destruction in NOD mice may be a Th2-mediated event.

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