scholarly journals Genetic Restoration of Heme Oxygenase-1 Expression Protects from Type 1 Diabetes in NOD Mice

2019 ◽  
Vol 20 (7) ◽  
pp. 1676 ◽  
Author(s):  
Julien Pogu ◽  
Sotiria Tzima ◽  
Georges Kollias ◽  
Ignacio Anegon ◽  
Philippe Blancou ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Heme Oxygenase ◽  
Transcriptional Activation ◽  
Critical Role ◽  
Nod Mice ◽  
Lower Percentage ◽  
Heme Oxygenase 1 ◽  
Autoreactive T Cells

Antigen-presenting cells (APCs) including dendritic cells (DCs) play a critical role in the development of autoimmune diseases by presenting self-antigen to T-cells. Different signals modulate the ability of APCs to activate or tolerize autoreactive T-cells. Since the expression of heme oxygenase-1 (HO-1) by APCs has been associated with the tolerization of autoreactive T-cells, we hypothesized that HO-1 expression might be altered in APCs from autoimmune-prone non-obese diabetic (NOD) mice. We found that, compared to control mice, NOD mice exhibited a lower percentage of HO-1-expressing cells among the splenic DCs, suggesting an impairment of their tolerogenic functions. To investigate whether restored expression of HO-1 in APCs could alter the development of diabetes in NOD mice, we generated a transgenic mouse strain in which HO-1 expression can be specifically induced in DCs using a tetracycline-controlled transcriptional activation system. Mice in which HO-1 expression was induced in DCs exhibited a lower Type 1 Diabetes (T1D) incidence and a reduced insulitis compared to non-induced mice. Upregulation of HO-1 in DCs also prevented further increase of glycemia in recently diabetic NOD mice. Altogether, our data demonstrated the potential of induction of HO-1 expression in DCs as a preventative treatment, and potential as a curative approach for T1D.

scholarly journals Systemic Expression of Heme Oxygenase-1 Ameliorates Type 1 Diabetes in NOD Mice

Diabetes ◽  
2007 ◽  
Vol 56 (5) ◽  
pp. 1240-1247 ◽  
Author(s):  
C.-M. Hu ◽  
H.-H. Lin ◽  
M.-T. Chiang ◽  
P.-F. Chang ◽  
L.-Y. Chau
Keyword(s):  
Type 1 Diabetes ◽  
Heme Oxygenase ◽  
Nod Mice ◽  
Heme Oxygenase 1

scholarly journals Lower Frequency of CD62Lhighand Higher Frequency of TNFR2+Tregs Are Associated with Inflammatory Conditions in Type 1 Diabetic Patients

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Monika Ryba ◽  
Karolina Rybarczyk-Kapturska ◽  
Katarzyna Zorena ◽  
Małgorzata Myśliwiec ◽  
Jolanta Myśliwska
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Regulatory T Cells ◽  
Lower Percentage ◽  
Diabetic Patients ◽  
Autoreactive T Cells ◽  
Inflammatory Conditions ◽  
Type 1 Diabetic Patients ◽  
Chronic Autoimmune Disease

Diabetes type 1 is a chronic autoimmune disease in which insulin-producing cells are gradually destroyed by autoreactive T cells. Human regulatory cells play important role in controlling autoimmunity, and their qualitative or quantitative dysfunctions may result in ineffective suppression of autoreactive T cells. CD62L is a surface molecule that plays role in homing capabilities of Tregs, and only cells with high expression of CD62L have high suppressive potential. Tregs are also characterized by the constant expression of TNFR2. The frequency of Tregs carrying TNFR2 is higher in inflammatory conditions. We investigated blood regulatory T cells with CD62L expression and regulatory T cells expressing TNFR2 in type 1 diabetic patients. We found differences in these populations when comparing to healthy individuals. We propose that these may be associated with inflammatory conditions that are present in patients with type 1 diabetes. The lower percentage of Tregs and Treg CD62Lhighmay contribute to ineffective suppression of proinflammatory cytokines production during type 1 diabetes.

scholarly journals Evidence for In Vivo Primed and Expanded Autoreactive T Cells as a Specific Feature of Patients with Type 1 Diabetes

2007 ◽  
Vol 179 (9) ◽  
pp. 5785-5792 ◽  
Author(s):  
Paolo Monti ◽  
Miriam Scirpoli ◽  
Andrea Rigamonti ◽  
Anya Mayr ◽  
Annika Jaeger ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Autoreactive T Cells

scholarly journals Variation in the CTLA4 3′UTR has phenotypic consequences for autoreactive T cells and associates with genetic risk for type 1 diabetes

2015 ◽  
Vol 17 (1) ◽  
pp. 75-78 ◽  
Author(s):  
V M de Jong ◽  
A Zaldumbide ◽  
A R van der Slik ◽  
S Laban ◽  
B P C Koeleman ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Genetic Risk ◽  
Autoreactive T Cells

scholarly journals Position β57 of I-Ag7 controls early anti-insulin responses in NOD mice, linking an MHC susceptibility allele to type 1 diabetes onset

2019 ◽  
Vol 4 (38) ◽  
pp. eaaw6329 ◽  
Author(s):  
Louis Gioia ◽  
Marie Holt ◽  
Anne Costanzo ◽  
Siddhartha Sharma ◽  
Brian Abe ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Disease Onset ◽  
Insulin Response ◽  
Nod Mice ◽  
Class Ii ◽  
Single Amino Acid ◽  
Specific Gene ◽  
Single Amino Acid Change

The class II region of the major histocompatibility complex (MHC) locus is the main contributor to the genetic susceptibility to type 1 diabetes (T1D). The loss of an aspartic acid at position 57 of diabetogenic HLA-DQβ chains supports this association; this single amino acid change influences how TCRs recognize peptides in the context of HLA-DQ8 and I-Ag7 using a mechanism termed the P9 switch. Here, we built register-specific insulin peptide MHC tetramers to examine CD4+ T cell responses to Ins12–20 and Ins13–21 peptides during the early prediabetic phase of disease in nonobese diabetic (NOD) mice. A single-cell analysis of anti-insulin CD4+ T cells performed in 6- and 12-week-old NOD mice revealed tissue-specific gene expression signatures. TCR signaling and clonal expansion were found only in the islets of Langerhans and produced either classical TH1 differentiation or an unusual Treg phenotype, independent of TCR usage. The early phase of the anti-insulin response was dominated by T cells specific for Ins12–20, the register that supports a P9 switch mode of recognition. The presence of the P9 switch was demonstrated by TCR sequencing, reexpression, mutagenesis, and functional testing of TCRαβ pairs in vitro. Genetic correction of the I-Aβ57 mutation in NOD mice resulted in the disappearance of D/E residues in the CDR3β of anti-Ins12–20 T cells. These results provide a mechanistic molecular explanation that links the characteristic MHC class II polymorphism of T1D with the recognition of islet autoantigens and disease onset.

scholarly journals Extending Remission and Reversing New-Onset Type 1 Diabetes by Targeted Ablation of Autoreactive T Cells

Diabetes ◽  
2018 ◽  
Vol 67 (11) ◽  
pp. 2319-2328
Author(s):  
Kaitlin R. Carroll ◽  
Eileen E. Elfers ◽  
Joseph J. Stevens ◽  
Jonathan P. McNally ◽  
David A. Hildeman ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Autoreactive T Cells ◽  
Onset Type ◽  
New Onset

Autoreactive T cells induce necrosis and not BCL-2-regulated or death receptor-mediated apoptosis or RIPK3-dependent necroptosis of transplanted islets in a mouse model of type 1 diabetes

Diabetologia ◽  
2014 ◽  
Vol 58 (1) ◽  
pp. 140-148 ◽  
Author(s):  
Yuxing Zhao ◽  
Nicholas A. Scott ◽  
Stacey Fynch ◽  
Lorraine Elkerbout ◽  
W. Wei-Lynn Wong ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Mouse Model ◽  
Death Receptor ◽  
Autoreactive T Cells
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