Upregulating CD4+CD25+FOXP3+ Regulatory T Cells in Pancreatic Lymph Nodes in Diabetic NOD Mice by Adjuvant Immunotherapy
Department of Surgery and Diabetes Institute for Immunology and Transplantation, University of Minnesota, Minneapolis, MN 55455, USA. Transplantation
(Impact Factor: 3.83).
02/2009; 87(2):198-206. DOI: 10.1097/TP.0b013e3181933261
Immunotherapy with Complete Freund's adjuvant (CFA) is effective in ameliorating autoimmunity in diabetic nonobese diabetic (NOD) mice. We investigated whether CFA treatment up-regulates CD4+CD25+Foxp3+ regulatory T cells and increases transforming growth factor (TGF)-beta1 production in diabetic NOD mice.
New-onset diabetic NOD mice were treated with CFA and exendin-4, a potent analog of glucagon-like peptide-1. Reversal of diabetes was determined by monitoring blood glucose level. Ameliorating autoimmunity through immunoregulation was assessed by adoptive transfer. Regulatory T cells in the peripheral blood, spleen, thymus, and pancreatic nodes were measured. TGF-beta1 in plasma and the insulin content in the pancreas were also measured. Immunostainings for insulin and BrdU were performed.
New-onset diabetes could be reversed in 38% of NOD mice treated with CFA alone and in 86% of NOD mice treated with both CFA and exendin-4. Diabetes adoptive transfer by splenocytes from CFA-treated NOD mice was delayed. The percentage of CD4+CD25+Foxp3+ regulatory T cells in the pancreatic lymph nodes of CFA-treated NOD mice was significantly increased at 1, 5, and 15 to 17 weeks after treatment. TGF-beta1 in the plasma of CFA-treated NOD mice was also significantly increased. Combining CFA with exendin-4 treatment significantly increased the insulin content and the numbers of insulin and BrdU double-labeled beta cells in the islets.
Our results demonstrated that CFA treatment ameliorates autoimmunity in diabetic NOD mice by up-regulating CD4=CD25+Foxp3+ regulatory T cells and increasing TGF-beta1 production. Exendin-4 enhanced the effect of CFA on reversing diabetes in NOD mice by stimulating beta-cell replication.
Available from: István Fodor
- "The protective effects of CFA were suggested to be mediated through the downregulation of autoreactive CTLs and the stimulation of NK cells. Most recent data however, demonstrate that CFA treatment ameliorates autoimmunity in NOD mice by up-regulating CD4 + CD25 + Foxp3 + regulatory T-cells in pancreatic lymph nodes and for increasing TGF-í µí»½1 production , in spite of the fact that altered frequencies of peripheral CD4 + CD25 + Foxp3 + regulatory Tcells were not yet shown to be specifically associated with type 1 diabetes . Molecular mechanisms involved in autoantigen-and adjuvant-dependant immune suppression detected in NOD mice remain to be further elucidated. "
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ABSTRACT: Data presented here demonstrate multifunctional vaccination strategies that harness vaccinia virus mediated delivery of a gene encoding an immunoenhanced diabetes autoantigen in combination with complete Freund's adjuvant (CFA) that can maintain safe and durable immunologic homeostasis in NOD mice. Systemic coinoculation of prediabetic mice with recombinant vaccinia virus rVV-CTB::GAD and undiluted or 10-fold diluted CFA demonstrated a significant decrease in hyperglycemia and pancreatic islet inflammation in comparison with control animals during 17-61 and 17-105 weeks of age, respectively. Synergy in these beneficial effects was observed during 43-61 and 61-105 wks of age, respectively. Inflammatory cytokine and chemokine levels in GAD-stimulated splenocytes isolated from vaccinated mice were generally lower than those detected in unvaccinated mice. The overall health and humoral immune responses of the vaccinated animals remained normal throughout the duration of the experiments.
Clinical and Developmental Immunology 11/2013; 2013(12):578786. DOI:10.1155/2013/578786 · 2.93 Impact Factor
Available from: Bhagirath Singh
- "The above feedback mechanism can explain the paradoxical finding that use of complete Freund's adjuvant (CFA) therapy raises inflammatory cytokines such as IFN-g and IL-17 while still being protective. This treatment also expands CD4 + CD25 + Foxp + T cells along inflammatory cytokines and establishes a new balance between regulatory and effector T cells with tolerogenic outcome (Tian and others 2009). We have shown the apoptosis of diabetogenic T cells in NOD mice by IFN-g and TNF-a as a mechanism of protection after mycobacterial adjuvant therapy (Qin and others 2004). "
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ABSTRACT: Juvenile or type 1 diabetes (T1D) involves autoimmune-mediated destruction of insulin-producing β cells in the islets of Langerhans in the pancreas. Lack of insulin prevents the absorption and metabolism of glucose throughout the body by interfering with cell signaling. Cytokines have been shown to play a key role in β cell destruction and regulation of autoimmunity in T1D. The multiple roles of cytokines in T1D pathogenesis, regulation, and regeneration of β cells presents both promise and challenge for their use in immunotherapy. We found that mycobacterial adjuvants induce various regulatory T cells in the non-obese diabetic (NOD) mouse model of T1D. Cytokines produced by these cells not only regulate innate and adaptive immunity but also prevent the development of diabetes and partially restored normoglycemia in diabetic NOD mice. We discovered that adjuvant immunotherapy upregulated Regenerating (Reg) genes in the islets and induced interleukin 22 (IL-22)-producing Th17 cells. IL-22 is known to upregulate Reg gene expression in islets and could potentially induce regeneration of β cells and prevent their apoptosis. Therefore, cytokines both induce and regulate T1D and have the potential to regenerate and preserve insulin-producing β cells in the islets.
Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research 08/2011; 31(10):711-9. DOI:10.1089/jir.2011.0025 · 2.00 Impact Factor
Available from: Garth Loren Warnock
- "Immunotherapy with CFA is effective in not only preventing spontaneous autoimmune diabetes, but also restoring self-tolerance to islet autoantigens. Recent studies conducted by Tian et al. (2009) demonstrated that CFA treatment ameliorates autoimmunity in diabetic NOD mice by up-regulating T regs and increasing TGF-β1 production. The percentage of T regs in the pancreatic lymph nodes of CFA-treated NOD mice was significantly increased at 1, 5, and 15 to 17 weeks after CFA treatment. "
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ABSTRACT: Type 1 diabetes (T1D) is the result of the autoimmune response against pancreatic insulin-producing ss-cells. Its ultimate consequence is beta-cell insufficiency-mediated dysregulation of blood glucose control. In terms of T1D treatment, immunotherapy addresses the cause of T1D, mainly through re-setting the balance between autoimmunity and regulatory mechanisms. Regulatory T cells play an important role in this immune intervention. An alternative T1D treatment is beta-cell replacement, which can reverse the consequence of the disease by replacing destroyed beta-cells in the diabetic pancreas. The applicable insulin-producing cells can be directly obtained from islet transplantation or generated from other cell sources such as autologous adult stem cells, embryonic stem cells, and induced pluripotent stem cells. In this review, we summarize the recent research progress and analyze the possible advantages and disadvantages of these two therapeutic options especially focusing on the potential synergistic effect on T1D treatment. Exploring the optimal combination of immunotherapy and beta-cell replacement will pave the way to the most effective cure for this devastating disease.
Life sciences 10/2009; 85(15-16):549-56. DOI:10.1016/j.lfs.2009.08.016 · 2.70 Impact Factor
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