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https://www.readbyqxmd.com/read/28550204/cutting-edge-origins-recruitment-and-regulation-of-cd11c-cells-in-inflamed-islets-of-autoimmune-diabetes-mice
#1
Joanna E Klementowicz, Ashley E Mahne, Allyson Spence, Vinh Nguyen, Ansuman T Satpathy, Kenneth M Murphy, Qizhi Tang
In NOD mice, CD11c(+) cells increase greatly with islet inflammation and contribute to autoimmune destruction of pancreatic β cells. In this study, we investigated their origin and mechanism of recruitment. CD11c(+) cells in inflamed islets resembled classical dendritic cells based on their transcriptional profile. However, the majority of these cells were not from the Zbtb46-dependent dendritic-cell lineage. Instead, monocyte precursors could give rise to CD11c(+) cells in inflamed islets. Chemokines Ccl5 and Ccl8 were persistently elevated in inflamed islets and the influx of CD11c(+) cells was partially dependent on their receptor Ccr5...
May 26, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28546003/thymic-epithelial-cell-specific-deletion-of-jmjd6-reduces-aire-protein-expression-and-exacerbates-disease-development-in-a-mouse-model-of-autoimmune-diabetes
#2
Toyoshi Yanagihara, Takahiro Tomino, Takehito Uruno, Yoshinori Fukui
Thymic epithelial cells (TECs) establish spatially distinct microenvironments in which developing T cells are selected to mature or die. A unique property of medullary TECs is their expression of thousands of tissue-restricted self-antigens that is largely under the control of the transcriptional regulator Aire. We previously showed that Jmjd6, a lysyl hydroxylase for splicing regulatory proteins, is important for Aire protein expression and that transplantation of Jmjd6-deficient thymic stroma into athymic nude mice resulted in multiorgan autoimmunity...
May 22, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28542921/cd40-mediated-signaling-influences-trafficking-tcr-expression-and-t-cell-pathogenesis-in-the-nod-model-of-type-1-diabetes
#3
Gisela M Vaitaitis, Dan M Waid, Martin G Yussman, David H Wagner
CD40 plays a critical role in the pathogenesis of type 1 diabetes (T1D). The mechanism of action however is undetermined, likely because CD40 expression has been grossly underestimated. CD40 is expressed on numerous cell types that now include T cells and pancreatic β cells. CD40(+) CD4(+) cells (TH40) prove highly pathogenic in NOD mice and in translational human T1D studies. We generated BDC2.5.CD40(-/-) and re-derived NOD.CD154(-/-) mice to better understand CD40 mechanism of action. Fully functional CD40 expression is required not only for T1D development but for insulitis...
May 19, 2017: Immunology
https://www.readbyqxmd.com/read/28539428/cutting-edge-dual-tcr%C3%AE-expression-poses-an-autoimmune-hazard-by-limiting-regulatory-t-cell-generation
#4
Nathaniel J Schuldt, Jennifer L Auger, Justin A Spanier, Tijana Martinov, Elise R Breed, Brian T Fife, Kristin A Hogquist, Bryce A Binstadt
Despite accounting for 10-30% of the T cell population in mice and humans, the role of dual TCR-expressing T cells in immunity remains poorly understood. It has been hypothesized that dual TCR T cells pose an autoimmune hazard by allowing self-reactive TCRs to escape thymic selection. We revisited this hypothesis using the NOD murine model of type 1 diabetes. We bred NOD mice hemizygous at both TCRα and β (TCRα(+/-) β(+/-)) loci, rendering them incapable of producing dual TCR T cells. We found that the lack of dual TCRα expression skewed the insulin-specific thymocyte population toward greater regulatory T (Treg) cell commitment, resulting in a more tolerogenic Treg to conventional T cell ratio and protection from diabetes...
May 24, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28536240/reply-to-tolerogenic-insulin-peptide-therapy-precipitates-type-1-diabetes
#5
Carolin Daniel, Benno Weigmann, Harald von Boehmer
In this issue of JEM, Bergman et al. (https://doi.org/10.1084/jem.20160471) challenge the data published in our previous JEM paper on the preventive effect of tolerogenic vaccination with a strong agonist insulin mimetope in type 1 diabetes. Here, we provide a response to these data and suggest that appropriate subimmunogenic conditions are required to induce Foxp3(+) regulatory T cell conversion.
May 23, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28534310/combination-immunotherapy-for-type-1-diabetes
#6
REVIEW
Robert N Bone, Carmella Evans-Molina
PURPOSE OF REVIEW: Type 1 diabetes (T1D) is an autoimmune disease marked by β-cell destruction. Immunotherapies for T1D have been investigated since the 1980s and have focused on restoration of tolerance, T cell or B cell inhibition, regulatory T cell (Treg) induction, suppression of innate immunity and inflammation, immune system reset, and islet transplantation. The purpose of this review is to provide an overview and lessons learned from single immunotherapy trials, describe recent and ongoing combination immunotherapy trials, and provide perspectives on strategies for future combination clinical interventions aimed at preserving insulin secretion in T1D...
July 2017: Current Diabetes Reports
https://www.readbyqxmd.com/read/28529840/adoptive-cell-therapy-with-tregs-to-improve-transplant-outcomes-the-promise-and-the-stumbling-blocks
#7
Mohamed B Ezzelarab, Angus W Thomson
The contribution of regulatory T cells (Treg) to the induction and maintenance of tolerance is well-recognized in rodents and may contribute to long-term human organ allograft survival. The therapeutic efficacy of adoptively-transferred Treg in promoting tolerance to organ allografts is well-recognized in mouse models. Early phase 1/2 clinical studies of Treg therapy have been conducted in patients with type-1 (autoimmune) diabetes and refractory Crohn's disease, and for inhibition of graft-versus-host disease following bone marrow transplantation with proven safety...
December 2016: Current Transplantation Reports
https://www.readbyqxmd.com/read/28512194/ancient-antagonism-between-celf-and-rbfox-families-tunes-mrna-splicing-outcomes
#8
Matthew R Gazzara, Michael J Mallory, Renat Roytenberg, John Lindberg, Anupama Jha, Kristen W Lynch, Yoseph Barash
Over 95% of human multi-exon genes undergo alternative splicing, a process important in normal development and often dysregulated in disease. We sought to analyze the global splicing regulatory network of CELF2 in human T cells, a well-studied splicing regulator critical to T cell development and function. By integrating high-throughput sequencing data for binding and splicing quantification with sequence features and probabilistic splicing code models, we find evidence of splicing antagonism between CELF2 and the RBFOX family of splicing factors...
May 16, 2017: Genome Research
https://www.readbyqxmd.com/read/28506774/immunomodulatory-and-protective-effects-of-adipose-tissue-derived-mesenchymal-stem-cells-in-an-allograft-islet-composite-transplantation-for-experimental-autoimmune-type-1-diabetes
#9
Jamal Mohammadi Ayenehdeh, Bahare Niknam, Shim Rasouli, Seyed Mahmoud Hashemi, Hossein Rahavi, Nima Rezaei, Masoud Soleimani, Ali Liaeiha, Mohammad Hossein Niknam, Nader Tajik
BACKGROUND: Allogeneic islet transplantation could be an ideal alternative therapy for Type 1 Diabetes Mellitus (T1DM). Adipose Tissue-derived Mesenchymal Stem Cells (AT-MSCs) characterized by immunomodulatory and protective effects may have the potential to improve the outcome of this highly immunogenic transplant. METHODS: Syngenic AT-MSCs along with allograft islets embedded in hydrogelic composite and transplanted intraperitoneally in Streptozotocin (STZ) induced diabetic C57BL/6 mice...
May 12, 2017: Immunology Letters
https://www.readbyqxmd.com/read/28496193/exendin-4-exhibits-enhanced-anti-tumor-effects-in-diabetic-mice
#10
Lan He, Priscilla T Y Law, Chun Kwok Wong, Juliana C N Chan, Paul K S Chan
Type 2 diabetes (T2D) is associated with increased risk of cancers. In this connection, we previously demonstrated the promoting effect of diabetes on HPV-associated carcinogenesis using a xenograft model in db/db diabetic mice. The underlying mechanism of this observation might be partly contributed by dysregulated immune response in diabetes. In this study, we hypothesized that the impaired anti-tumor immune response in diabetic status could be modulated by exendin-4, a glucagon-like protein receptor agonist which exhibits anti-diabetic effects...
May 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28467828/dominant-protection-from-hla-linked-autoimmunity-by-antigen-specific-regulatory-t-cells
#11
Joshua D Ooi, Jan Petersen, Yu H Tan, Megan Huynh, Zoe J Willett, Sri H Ramarathinam, Peter J Eggenhuizen, Khai L Loh, Katherine A Watson, Poh Y Gan, Maliha A Alikhan, Nadine L Dudek, Andreas Handel, Billy G Hudson, Lars Fugger, David A Power, Stephen G Holt, P Toby Coates, Jon W Gregersen, Anthony W Purcell, Stephen R Holdsworth, Nicole L La Gruta, Hugh H Reid, Jamie Rossjohn, A Richard Kitching
Susceptibility and protection against human autoimmune diseases, including type I diabetes, multiple sclerosis, and Goodpasture disease, is associated with particular human leukocyte antigen (HLA) alleles. However, the mechanisms underpinning such HLA-mediated effects on self-tolerance remain unclear. Here we investigate the molecular mechanism of Goodpasture disease, an HLA-linked autoimmune renal disorder characterized by an immunodominant CD4(+) T-cell self-epitope derived from the α3 chain of type IV collagen (α3135-145)...
May 11, 2017: Nature
https://www.readbyqxmd.com/read/28461573/genetic-and-small-molecule-disruption-of-the-aid-rad51-axis-similarly-protects-nonobese-diabetic-mice-from-type-1-diabetes-through-expansion-of-regulatory-b-lymphocytes
#12
Jeremy J Ratiu, Jeremy J Racine, Muneer G Hasham, Qiming Wang, Jane A Branca, Harold D Chapman, Jing Zhu, Nina Donghia, Vivek Philip, William H Schott, Clive Wasserfall, Mark A Atkinson, Kevin D Mills, Caroline M Leeth, David V Serreze
B lymphocytes play a key role in type 1 diabetes (T1D) development by serving as a subset of APCs preferentially supporting the expansion of autoreactive pathogenic T cells. As a result of their pathogenic importance, B lymphocyte-targeted therapies have received considerable interest as potential T1D interventions. Unfortunately, the B lymphocyte-directed T1D interventions tested to date failed to halt β cell demise. IgG autoantibodies marking humans at future risk for T1D indicate that B lymphocytes producing them have undergone the affinity-maturation processes of class switch recombination and, possibly, somatic hypermutation...
May 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28450863/the-proteasome-inhibitor-bortezomib-controls-indoleamine-2-3-dioxygenase-1-breakdown-and-restores-immune-regulation-in-autoimmune-diabetes
#13
Giada Mondanelli, Elisa Albini, Maria T Pallotta, Claudia Volpi, Lucienne Chatenoud, Chantal Kuhn, Francesca Fallarino, Davide Matino, Maria L Belladonna, Roberta Bianchi, Carmine Vacca, Silvio Bicciato, Louis Boon, Giovanni Ricci, Ursula Grohmann, Paolo Puccetti, Ciriana Orabona
Bortezomib (BTZ) is a first-in-class proteasome inhibitor approved for the therapy of multiple myeloma that also displays unique regulatory activities on immune cells. The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is a tryptophan metabolizing enzyme exerting potent immunoregulatory effects when expressed in dendritic cells (DCs), the most potent antigen-presenting cells capable of promoting either immunity or tolerance. We previously demonstrated that, in inflammatory conditions, IDO1 is subjected to proteasomal degradation in DCs, turning these cells from immunoregulatory to immunostimulatory...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28448894/il-33-improves-the-suppressive-potential-of-regulatory-t-cells-in-patients-with-type-1-diabetes
#14
Monika Ryba-Stanisławowska, Laura Buksa, Agnieszka Brandt, Ulana Juhas, Małgorzata Myśliwiec
AIMS: The presented study was aimed to analyze the influence of IL-33 on regulatory T cells (Tregs) suppressive potential in patients with type 1 diabetes. METHODS: We analyzed the ability of IL-33 treated Tregs to inhibit the production of IFN-γ by effector T lymphocytes in an in vitro co-culture. The study group consisted of 22 patients with type 1 diabetes and 12 age and sex-matched healthy individuals. RESULTS: Our findings revealed that in vitro IL-33 treatment of Tregs derived from patients with type 1 diabetes resulted in quantitative as well as qualitative changes in this cell population, confirming immunoregulatory features of IL-33...
April 13, 2017: Diabetes Research and Clinical Practice
https://www.readbyqxmd.com/read/28439004/endocannabinoid-system-acts-as-a-regulator-of-immune-homeostasis-in-the-gut
#15
Nandini Acharya, Sasi Penukonda, Tatiana Shcheglova, Adam T Hagymasi, Sreyashi Basu, Pramod K Srivastava
Endogenous cannabinoids (endocannabinoids) are small molecules biosynthesized from membrane glycerophospholipid. Anandamide (AEA) is an endogenous intestinal cannabinoid that controls appetite and energy balance by engagement of the enteric nervous system through cannabinoid receptors. Here, we uncover a role for AEA and its receptor, cannabinoid receptor 2 (CB2), in the regulation of immune tolerance in the gut and the pancreas. This work demonstrates a major immunological role for an endocannabinoid. The pungent molecule capsaicin (CP) has a similar effect as AEA; however, CP acts by engagement of the vanilloid receptor TRPV1, causing local production of AEA, which acts through CB2...
May 9, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28420440/immune-response-after-autologous-hematopoietic-stem-cell-transplantation-in-type-1-diabetes-mellitus
#16
Lei Ye, Li Li, Bing Wan, Minglan Yang, Jie Hong, Weiqiong Gu, Weiqing Wang, Guang Ning
BACKGROUND: This study explored the details of the immune response after autologous hematopoietic stem cell transplantation (AHSCT) treatment in type 1 diabetes mellitus. METHODS: Peripheral blood mononuclear cells (PBMCs) from 18 patients with type 1 diabetes mellitus were taken at baseline and 12 months after AHSCT or insulin-only therapy. The lymphocyte proliferation, mRNA expression and secretion of pro-inflammatory and anti-inflammatory cytokines belonging to T-helper type 1 (Th1), T-helper type 17 (Th17) and regulatory T (Treg) cells in PBMC culture supernatants were assessed...
April 18, 2017: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/28413863/metabolism-and-homeostasis-in-the-kidney-metabolic-regulation-through-insulin-signaling-in-the-kidney
#17
REVIEW
Alexander Kuczkowski, Paul T Brinkkoetter
Metabolic signaling pathways orchestrate the dynamic turnover between catabolic and anabolic processes. Thereby, they ensure the viability of the cell and assure proper function of the tissue in changing environments regarding the availability of nutrients. Yet, renal cells are not considered to be prime targets of metabolic signaling. Research of the last decade has proposed new roles of specifically altered metabolic signaling pathways. In particular, the insulin signaling cascade, a potent regulator of cellular metabolism and energy homeostasis, seems to be implicated in the progression of diabetic and non-diabetic kidney disease...
April 17, 2017: Cell and Tissue Research
https://www.readbyqxmd.com/read/28403169/osteopontin-activates-the-diabetes-associated-potassium-channel-talk-1-in-pancreatic-%C3%AE-cells
#18
Matthew T Dickerson, Nicholas C Vierra, Sarah C Milian, Prasanna K Dadi, David A Jacobson
Glucose-stimulated insulin secretion (GSIS) relies on β-cell Ca2+ influx, which is modulated by the two-pore-domain K+ (K2P) channel, TALK-1. A gain-of-function polymorphism in KCNK16, the gene encoding TALK-1, increases risk for developing type-2 diabetes. While TALK-1 serves an important role in modulating GSIS, the regulatory mechanism(s) that control β-cell TALK-1 channels are unknown. Therefore, we employed a membrane-specific yeast two-hybrid (MYTH) assay to identify TALK-1-interacting proteins in human islets, which will assist in determining signaling modalities that modulate TALK-1 function...
2017: PloS One
https://www.readbyqxmd.com/read/28398495/a-histological-study-of-fulminant-type-1-diabetes-mellitus-related-to-human-cytomegalovirus-reactivation
#19
Sho Yoneda, Akihisa Imagawa, Kenji Fukui, Sae Uno, Junji Kozawa, Makoto Sakai, Toshiki Yumioka, Hiromi Iwahashi, Iichiro Shimomura
Context: Fulminant type 1 diabetes mellitus (T1DM) is thought to be partly caused by virus infection. Objective: This study investigated the mechanism of β cell destruction in fulminant T1DM after drug-induced hypersensitivity syndrome (DIHS). Methods: We determined the localization of viruses of human cytomegalovirus (HCMV), human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV), and the expression of interferon regulatory factor 3 (IRF3) and viral receptors of Z DNA binding protein 1 (ZBP1) and retinoic acid-inducible gene I (RIG-I), together with inflammatory cells by immunohistochemistry of pancreas from an autopsy fulminant T1DM patient with DIHS or seven subjects with normal glucose tolerance who underwent pancreatectomy...
April 10, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28396406/flicr-a-long-noncoding-rna-modulates-foxp3-expression-and-autoimmunity
#20
David Zemmour, Alvin Pratama, Scott M Loughhead, Diane Mathis, Christophe Benoist
A combination of transcription factors, enhancers, and epigenetic marks determines the expression of the key transcription factor FoxP3 in regulatory T cells (Tregs). Adding an additional layer of complexity, the long noncoding RNA (lncRNA) Flicr (Foxp3 long intergenic noncoding RNA) is a negative regulator that tunes Foxp3 expression, resulting in a subset of Tregs with twofold- to fivefold-lower levels of FoxP3 protein. The impact of Flicr is particularly marked in conditions of IL-2 deficiency, and, conversely, IL-2 represses Flicr expression...
April 25, 2017: Proceedings of the National Academy of Sciences of the United States of America
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