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Oxidative stress and redox modulation potential in type 1 diabetes.

Delmastro MM, Piganelli JD - Clin. Dev. Immunol. (2011)

Bottom Line: Activated macrophages/DCs ferry β-cell antigens specifically to pancreatic lymph nodes, where they trigger reactive T cells through synapse formation and secretion of proinflammatory cytokines and more ROS.ROS generation, therefore, is pivotal in formulating both innate and adaptive immune responses accountable for islet cell autoimmunity.The importance of ROS/oxidative stress as well as potential for redox modulation in the context of T1D will be discussed.

View Article: PubMed Central - PubMed

Affiliation: Diabetes Institute, Division of Immunogenetics, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.

ABSTRACT
Redox reactions are imperative to preserving cellular metabolism yet must be strictly regulated. Imbalances between reactive oxygen species (ROS) and antioxidants can initiate oxidative stress, which without proper resolve, can manifest into disease. In type 1 diabetes (T1D), T-cell-mediated autoimmune destruction of pancreatic β-cells is secondary to the primary invasion of macrophages and dendritic cells (DCs) into the islets. Macrophages/DCs, however, are activated by intercellular ROS from resident pancreatic phagocytes and intracellular ROS formed after receptor-ligand interactions via redox-dependent transcription factors such as NF-κB. Activated macrophages/DCs ferry β-cell antigens specifically to pancreatic lymph nodes, where they trigger reactive T cells through synapse formation and secretion of proinflammatory cytokines and more ROS. ROS generation, therefore, is pivotal in formulating both innate and adaptive immune responses accountable for islet cell autoimmunity. The importance of ROS/oxidative stress as well as potential for redox modulation in the context of T1D will be discussed.

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Related in: MedlinePlus

Role of redox modulation in controlling ROS-mediated beta cell destruction. Redox modulation has shown promise in blocking the production of ROS and its ability to activate APCs, resulting in diminished TH1 cell activation and effector function, which ultimately may help regulate beta-cell destruction.
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Related In: Results  -  Collection


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fig2: Role of redox modulation in controlling ROS-mediated beta cell destruction. Redox modulation has shown promise in blocking the production of ROS and its ability to activate APCs, resulting in diminished TH1 cell activation and effector function, which ultimately may help regulate beta-cell destruction.

Mentions: The activation of macrophages and T cells relies on oxidative stress, which ultimately leads to the progression of T1D. Based upon this fact, CA was also investigated in the context of CD4 and CD8 T cells. The BDC-2.5 TCR-Tg TH1 cell clone, which has recently been described as specific for the protein ChgA, a member of the granin family of neuroendocrine secretory proteins [183], causes rapid transfer of diabetes into NOD.scid recipients [184]. By utilizing this method, pretreatment of NOD.scid mice with CA prior to adoptive transfer of the BDC-2.5 clone inhibits the infiltration of T cells into the pancreas, significantly delaying T1D onset. Moreover, APC-dependent BDC-2.5 T cell proliferation and IFNγ production are also reduced after in vitro CA treatment [25]. To further delineate the mechanism of diminished T-cell effector function, in vivo treatment of NOD and BDC-2.5 TCR-Tg mice with CA was able to decrease innate-derived third signal synthesis, primarily consisting of TNFα, resulting in antigen-specific T cell hyporesponsiveness [37]. Similar results were found upon CA treatment in the context of CD8 T cells, reducing proliferation, cytokine production, and cytolytic effector molecules of CTLs [185]. Interestingly, by inhibiting NADPH oxidase in NOD animals (NOD.Ncf1m1J) in an effort to genetically mimic systemic CA administration, not only is NOX-derived superoxide production eliminated, but T cells show reduced TH1 responses, granting protection from T1D onset [120]. Earlier studies by Chaudhri et al. supported our experimentation by demonstrating attenuation of T-cell proliferation and IL-2R expression following antioxidant treatment [186, 187]. Such findings point to the possibility and importance of redox modulation in not only regulating the innate immune cells, but also impacting the T cells which formulate an adaptive immune response crucial for the autoimmune attack in T1D (Figure 2).


Oxidative stress and redox modulation potential in type 1 diabetes.

Delmastro MM, Piganelli JD - Clin. Dev. Immunol. (2011)

Role of redox modulation in controlling ROS-mediated beta cell destruction. Redox modulation has shown promise in blocking the production of ROS and its ability to activate APCs, resulting in diminished TH1 cell activation and effector function, which ultimately may help regulate beta-cell destruction.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3102468&req=5

fig2: Role of redox modulation in controlling ROS-mediated beta cell destruction. Redox modulation has shown promise in blocking the production of ROS and its ability to activate APCs, resulting in diminished TH1 cell activation and effector function, which ultimately may help regulate beta-cell destruction.
Mentions: The activation of macrophages and T cells relies on oxidative stress, which ultimately leads to the progression of T1D. Based upon this fact, CA was also investigated in the context of CD4 and CD8 T cells. The BDC-2.5 TCR-Tg TH1 cell clone, which has recently been described as specific for the protein ChgA, a member of the granin family of neuroendocrine secretory proteins [183], causes rapid transfer of diabetes into NOD.scid recipients [184]. By utilizing this method, pretreatment of NOD.scid mice with CA prior to adoptive transfer of the BDC-2.5 clone inhibits the infiltration of T cells into the pancreas, significantly delaying T1D onset. Moreover, APC-dependent BDC-2.5 T cell proliferation and IFNγ production are also reduced after in vitro CA treatment [25]. To further delineate the mechanism of diminished T-cell effector function, in vivo treatment of NOD and BDC-2.5 TCR-Tg mice with CA was able to decrease innate-derived third signal synthesis, primarily consisting of TNFα, resulting in antigen-specific T cell hyporesponsiveness [37]. Similar results were found upon CA treatment in the context of CD8 T cells, reducing proliferation, cytokine production, and cytolytic effector molecules of CTLs [185]. Interestingly, by inhibiting NADPH oxidase in NOD animals (NOD.Ncf1m1J) in an effort to genetically mimic systemic CA administration, not only is NOX-derived superoxide production eliminated, but T cells show reduced TH1 responses, granting protection from T1D onset [120]. Earlier studies by Chaudhri et al. supported our experimentation by demonstrating attenuation of T-cell proliferation and IL-2R expression following antioxidant treatment [186, 187]. Such findings point to the possibility and importance of redox modulation in not only regulating the innate immune cells, but also impacting the T cells which formulate an adaptive immune response crucial for the autoimmune attack in T1D (Figure 2).

Bottom Line: Activated macrophages/DCs ferry β-cell antigens specifically to pancreatic lymph nodes, where they trigger reactive T cells through synapse formation and secretion of proinflammatory cytokines and more ROS.ROS generation, therefore, is pivotal in formulating both innate and adaptive immune responses accountable for islet cell autoimmunity.The importance of ROS/oxidative stress as well as potential for redox modulation in the context of T1D will be discussed.

View Article: PubMed Central - PubMed

Affiliation: Diabetes Institute, Division of Immunogenetics, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.

ABSTRACT
Redox reactions are imperative to preserving cellular metabolism yet must be strictly regulated. Imbalances between reactive oxygen species (ROS) and antioxidants can initiate oxidative stress, which without proper resolve, can manifest into disease. In type 1 diabetes (T1D), T-cell-mediated autoimmune destruction of pancreatic β-cells is secondary to the primary invasion of macrophages and dendritic cells (DCs) into the islets. Macrophages/DCs, however, are activated by intercellular ROS from resident pancreatic phagocytes and intracellular ROS formed after receptor-ligand interactions via redox-dependent transcription factors such as NF-κB. Activated macrophages/DCs ferry β-cell antigens specifically to pancreatic lymph nodes, where they trigger reactive T cells through synapse formation and secretion of proinflammatory cytokines and more ROS. ROS generation, therefore, is pivotal in formulating both innate and adaptive immune responses accountable for islet cell autoimmunity. The importance of ROS/oxidative stress as well as potential for redox modulation in the context of T1D will be discussed.

Show MeSH
Related in: MedlinePlus