The Experts below are selected from a list of 135 Experts worldwide ranked by ideXlab platform
Richard A. Flavell - One of the best experts on this subject based on the ideXlab platform.
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CD4+CD25+ T regulatory cells control anti-islet CD8+ T cells through TGF-β–TGF-β receptor interactions in type 1 diabetes
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: E. Allison Green, Leonid Gorelik, Catrin M. Mcgregor, Elise H. Tran, Richard A. FlavellAbstract:Pancreatic Lymph Node-derived CD4+CD25+ T regulatory (Treg) cells inhibit in situ differentiation of islet-reactive CD8+ T cells into cytotoxic T Lymphocytes, thereby preventing diabetes progression. The mechanism by which these Treg cells suppress anti-islet CD8+ T cells is unknown. Here, we show by using a CD8+ T cell-mediated model of type 1 diabetes that transforming growth factor (TGF)-β–TGF-β receptor signals are critical for CD4+CD25+ Treg cell regulation of autoreactive islet-specific cytotoxic T Lymphocytes. Transgenic expression of tumor necrosis factor α from birth to 25 days of age in the islets of B6 mice that constitutively express CD80 on their β cells results in accumulation of CD4+CD25+TGF-β+ cells exclusively in the islets and Pancreatic Lymph Nodes, which delays diabetes progression. In contrast, expression of tumor necrosis factor α until 28 days of age prevents islet accumulation of CD4+CD25+TGF-β+ Treg cells, resulting in acceleration to diabetes. Furthermore, adoptive transfer experiments demonstrated that CD4+CD25+ Treg cells could not control naive or activated isletreactive CD8+ T cells bearing a dominant negative TGF-β receptor type II. Our data demonstrate that, in vivo, TGF-β signaling in CD8+ T cells is critical for CD4+CD25+ Treg cell suppression of isletreactive CD8+ T cells in type 1 diabetes.
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Pancreatic Lymph Node derived cd4 cd25 treg cells highly potent regulators of diabetes that require trance rank signals
Immunity, 2002Co-Authors: Allison E Green, Yongwon Choi, Richard A. FlavellAbstract:Inflammation can activate self-reactive CD8(+) T cells and induce autoimmunity. Here we show in a CD8(+) T cell-mediated model of type 1 diabetes that CD4(+)CD25(+) Treg cells prevent beta cell destruction following localized inflammation in the islets of Langerhans. These Treg cells accumulate preferentially in the Pancreatic Lymph Nodes and islets but not other Lymph Nodes or spleen. PLN-derived Treg cells are extremely potent; only 2 x 10(3) cells are needed to prevent diabetes development, and their capacity to regulate is dependent on TNF-related activation induced cytokine-receptor activator of NFkappaB signals. Indeed, blockade of this pathway results in decreased frequency of CD4(+)CD25(+) Treg cells in the PLN, resulting in intra-islet differentiation of CD8(+) T cells into CTLs and rapid progression to diabetes.
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Pancreatic Lymph Node-Derived CD4+CD25+ Treg Cells: Highly Potent Regulators of Diabetes that Require TRANCE-RANK Signals
Immunity, 2002Co-Authors: E. Allison Green, Yongwon Choi, Richard A. FlavellAbstract:Inflammation can activate self-reactive CD8(+) T cells and induce autoimmunity. Here we show in a CD8(+) T cell-mediated model of type 1 diabetes that CD4(+)CD25(+) Treg cells prevent beta cell destruction following localized inflammation in the islets of Langerhans. These Treg cells accumulate preferentially in the Pancreatic Lymph Nodes and islets but not other Lymph Nodes or spleen. PLN-derived Treg cells are extremely potent; only 2 x 10(3) cells are needed to prevent diabetes development, and their capacity to regulate is dependent on TNF-related activation induced cytokine-receptor activator of NFkappaB signals. Indeed, blockade of this pathway results in decreased frequency of CD4(+)CD25(+) Treg cells in the PLN, resulting in intra-islet differentiation of CD8(+) T cells into CTLs and rapid progression to diabetes.
Michael J. Clare-salzler - One of the best experts on this subject based on the ideXlab platform.
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Dual-Sized Microparticle System for Generating Suppressive Dendritic Cells Prevents and Reverses Type 1 Diabetes in the Nonobese Diabetic Mouse Model.
ACS biomaterials science & engineering, 2019Co-Authors: Jamal S. Lewis, Joshua M. Stewart, Gregory P. Marshall, Matthew R. Carstens, Ying Zhang, Natalia V. Dolgova, Chang-qing Xia, Todd M. Brusko, Clive Wasserfall, Michael J. Clare-salzlerAbstract:Antigen specificity is a primary goal in developing curative therapies for autoimmune disease. Dendritic cells (DCs), as the most effective antigen presenting cells in the body, represent a key target to mediate restoration of antigen-specific immune regulation. Here, we describe an injectable, dual-sized microparticle (MP) approach that employs phagocytosable ∼1 μm and nonphagocytosable ∼30 μm MPs to deliver tolerance-promoting factors both intracellularly and extracellularly, as well as the type 1 diabetes autoantigen, insulin, to DCs for reprogramming of immune responses and remediation of autoimmunity. This poly(lactic-co-glycolic acid) (PLGA) MP system prevented diabetes onset in 60% of nonobese diabetic (NOD) mice when administered subcutaneously in 8 week old mice. Prevention of disease was dependent upon antigen inclusion and required encapsulation of factors in MPs. Moreover, administration of this “suppressive-vaccine” boosted Pancreatic Lymph Node and splenic regulatory T cells (Tregs), upregul...
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Dual-Sized Microparticle System for Generating Suppressive Dendritic Cells Prevents and Reverses Type 1 Diabetes in the Nonobese Diabetic Mouse Model
2019Co-Authors: Jamal S. Lewis, Joshua M. Stewart, Gregory P. Marshall, Matthew R. Carstens, Ying Zhang, Natalia V. Dolgova, Chang-qing Xia, Todd M. Brusko, Clive Wasserfall, Michael J. Clare-salzlerAbstract:Antigen specificity is a primary goal in developing curative therapies for autoimmune disease. Dendritic cells (DCs), as the most effective antigen presenting cells in the body, represent a key target to mediate restoration of antigen-specific immune regulation. Here, we describe an injectable, dual-sized microparticle (MP) approach that employs phagocytosable ∼1 μm and nonphagocytosable ∼30 μm MPs to deliver tolerance-promoting factors both intracellularly and extracellularly, as well as the type 1 diabetes autoantigen, insulin, to DCs for reprogramming of immune responses and remediation of autoimmunity. This poly(lactic-co-glycolic acid) (PLGA) MP system prevented diabetes onset in 60% of nonobese diabetic (NOD) mice when administered subcutaneously in 8 week old mice. Prevention of disease was dependent upon antigen inclusion and required encapsulation of factors in MPs. Moreover, administration of this “suppressive-vaccine” boosted Pancreatic Lymph Node and splenic regulatory T cells (Tregs), upregulated PD-1 on CD4+ and CD8+ T cells, and reversed hyperglycemia for up to 100 days in recent-onset NOD mice. Our results demonstrate that a MP-based platform can reeducate the immune system in an antigen-specific manner, augment immunomodulation compared to soluble administration of drugs, and provide a promising alternative to systemic immunosuppression for autoimmunity
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Marked dendritic cell-T cell cluster formation in the Pancreatic Lymph Node of the non-obese diabetic mouse.
Immunology, 1992Co-Authors: Michael J. Clare-salzler, Yoko MullenAbstract:Dendritic cells (DC) isolated from various Lymph Node (LN) groups of pre-diabetic non-obese diabetic (NOD) (4-20 weeks of age) and age-sex-matched control mice were analysed for their surface antigen phenotype and their ability to cluster Lymphocytes. The draining LN of the pancreas (PLN) of 8-week-old NOD mice with active autoimmune disease were significantly enlarged in comparison to the axillary LN of the same NOD mice and the PLN from control mice. NOD DC isolated from PLN and other LN demonstrated classical DC morphology, were highly major histocompatibility complex (MHC) class II antigen positive, and were 50-70% 33D1+ (DC-specific antibody). In an assay for DC-T cell clustering, DC from the PLN of 8-20-week-old NOD formed large clusters (greater than 10 cells) with PLN cells at a frequency three to 20 times greater than that observed with DC and LN cells from the PLN of 8-week-old control mice, the PLN of 4-week-old NOD mice, and axillary/inguinal LN of 8-week-old NOD mice. Clustered cells were 80% Thy-1.2+ (56% L3T4, 17% Lyt-2+). Specificity of clustering was demonstrated as PLN DC clustered only PLN T cells in the assay; axillary/inguinal (A/I) DC added to PLN LC did not induce clustering nor did PLN DC induce clustering of the A/I population. Cell proliferation in isolated PLN DC/LC clusters was markedly greater than that of A/I clusters and of non-clustered PLN cells. These data demonstrate that DC from the PLN of NOD mice with active autoimmune disease form stable clusters with T cells from the PLN and these clusters are the major source of proliferating T cells in these LN. We hypothesize that PLN DC may play an important role in the autoimmune disease of the NOD mouse.
E. Allison Green - One of the best experts on this subject based on the ideXlab platform.
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CD4+CD25+ T regulatory cells control anti-islet CD8+ T cells through TGF-β–TGF-β receptor interactions in type 1 diabetes
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: E. Allison Green, Leonid Gorelik, Catrin M. Mcgregor, Elise H. Tran, Richard A. FlavellAbstract:Pancreatic Lymph Node-derived CD4+CD25+ T regulatory (Treg) cells inhibit in situ differentiation of islet-reactive CD8+ T cells into cytotoxic T Lymphocytes, thereby preventing diabetes progression. The mechanism by which these Treg cells suppress anti-islet CD8+ T cells is unknown. Here, we show by using a CD8+ T cell-mediated model of type 1 diabetes that transforming growth factor (TGF)-β–TGF-β receptor signals are critical for CD4+CD25+ Treg cell regulation of autoreactive islet-specific cytotoxic T Lymphocytes. Transgenic expression of tumor necrosis factor α from birth to 25 days of age in the islets of B6 mice that constitutively express CD80 on their β cells results in accumulation of CD4+CD25+TGF-β+ cells exclusively in the islets and Pancreatic Lymph Nodes, which delays diabetes progression. In contrast, expression of tumor necrosis factor α until 28 days of age prevents islet accumulation of CD4+CD25+TGF-β+ Treg cells, resulting in acceleration to diabetes. Furthermore, adoptive transfer experiments demonstrated that CD4+CD25+ Treg cells could not control naive or activated isletreactive CD8+ T cells bearing a dominant negative TGF-β receptor type II. Our data demonstrate that, in vivo, TGF-β signaling in CD8+ T cells is critical for CD4+CD25+ Treg cell suppression of isletreactive CD8+ T cells in type 1 diabetes.
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Pancreatic Lymph Node-Derived CD4+CD25+ Treg Cells: Highly Potent Regulators of Diabetes that Require TRANCE-RANK Signals
Immunity, 2002Co-Authors: E. Allison Green, Yongwon Choi, Richard A. FlavellAbstract:Inflammation can activate self-reactive CD8(+) T cells and induce autoimmunity. Here we show in a CD8(+) T cell-mediated model of type 1 diabetes that CD4(+)CD25(+) Treg cells prevent beta cell destruction following localized inflammation in the islets of Langerhans. These Treg cells accumulate preferentially in the Pancreatic Lymph Nodes and islets but not other Lymph Nodes or spleen. PLN-derived Treg cells are extremely potent; only 2 x 10(3) cells are needed to prevent diabetes development, and their capacity to regulate is dependent on TNF-related activation induced cytokine-receptor activator of NFkappaB signals. Indeed, blockade of this pathway results in decreased frequency of CD4(+)CD25(+) Treg cells in the PLN, resulting in intra-islet differentiation of CD8(+) T cells into CTLs and rapid progression to diabetes.
Yongwon Choi - One of the best experts on this subject based on the ideXlab platform.
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Pancreatic Lymph Node derived cd4 cd25 treg cells highly potent regulators of diabetes that require trance rank signals
Immunity, 2002Co-Authors: Allison E Green, Yongwon Choi, Richard A. FlavellAbstract:Inflammation can activate self-reactive CD8(+) T cells and induce autoimmunity. Here we show in a CD8(+) T cell-mediated model of type 1 diabetes that CD4(+)CD25(+) Treg cells prevent beta cell destruction following localized inflammation in the islets of Langerhans. These Treg cells accumulate preferentially in the Pancreatic Lymph Nodes and islets but not other Lymph Nodes or spleen. PLN-derived Treg cells are extremely potent; only 2 x 10(3) cells are needed to prevent diabetes development, and their capacity to regulate is dependent on TNF-related activation induced cytokine-receptor activator of NFkappaB signals. Indeed, blockade of this pathway results in decreased frequency of CD4(+)CD25(+) Treg cells in the PLN, resulting in intra-islet differentiation of CD8(+) T cells into CTLs and rapid progression to diabetes.
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Pancreatic Lymph Node-Derived CD4+CD25+ Treg Cells: Highly Potent Regulators of Diabetes that Require TRANCE-RANK Signals
Immunity, 2002Co-Authors: E. Allison Green, Yongwon Choi, Richard A. FlavellAbstract:Inflammation can activate self-reactive CD8(+) T cells and induce autoimmunity. Here we show in a CD8(+) T cell-mediated model of type 1 diabetes that CD4(+)CD25(+) Treg cells prevent beta cell destruction following localized inflammation in the islets of Langerhans. These Treg cells accumulate preferentially in the Pancreatic Lymph Nodes and islets but not other Lymph Nodes or spleen. PLN-derived Treg cells are extremely potent; only 2 x 10(3) cells are needed to prevent diabetes development, and their capacity to regulate is dependent on TNF-related activation induced cytokine-receptor activator of NFkappaB signals. Indeed, blockade of this pathway results in decreased frequency of CD4(+)CD25(+) Treg cells in the PLN, resulting in intra-islet differentiation of CD8(+) T cells into CTLs and rapid progression to diabetes.
Hugh O. Mcdevitt - One of the best experts on this subject based on the ideXlab platform.
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The role of TNF-α in the pathogenesis of type 1 diabetes in the nonobese diabetic mouse: Analysis of dendritic cell maturation
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Li-fen Lee, Sara A. Michie, Georg F. Beilhack, Tibor Warganich, Shannon J. Turley, Hugh O. McdevittAbstract:TNF-α has been linked to the development of type 1 diabetes (T1D). We previously reported that neonatal treatment of nonobese diabetic (NOD) mice with TNF-α accelerated the onset of T1D, whereas TNF-α blockade in the same time period resulted in a complete absence of diabetes. The mechanisms by which TNF-α modulates development of T1D in NOD mice remain unclear. Here we tested the effects of TNF-α on the maturation of dendritic cells (DCs) in the NOD mouse. We found that neonatal treatment with TNF-α caused an increase in expression of maturation markers on CD11c+CD11b+ DC subpopulations, whereas treatment with anti-TNF-α resulted in a decrease in expression of maturation markers in the CD11c+CD11b+ subset. Moreover, neonatal treatment with TNF-α resulted in skewed development of a CD8α+CD11b-CD11c+ DC subset such that TNF-α decreases the CD8α+CD11c+ DC subset, increases the CD11c+CD11b+ subset, and causes an increase in the expression of CD40 and CD54 on mature DCs capable of inducing immunity. Anti-TNF-α-treated mice had an increase in the CD8α+CD11c+ DCs. Notably, adoptively transferred naive CD4+ T cells from BDC2.5 T cell receptor transgenic mice proliferated in the Pancreatic Lymph Nodes in TNF-α-treated NOD mice but not in anti-TNF-α-treated mice. Finally, we show that anti-TNF-α-treated mice showed immunological tolerance to islet cell proteins. We conclude that TNF-α plays an important role in the initiation of T1D in the NOD mouse by regulating the maturation of DCs and, thus, the activation of islet-specific Pancreatic Lymph Node T cells.
