Auto-antigen and Immunomodulatory Agent–Based Approaches for Antigen-Specific Tolerance in NOD Mice

2021 ◽  
Vol 21 (3) ◽  
Author(s):  
Ethan J. Bassin ◽  
Jon D. Piganelli ◽  
Steven R. Little
Keyword(s):  
Nod Mice ◽  
Agent Based ◽  
Immunomodulatory Agent ◽  
Specific Tolerance

scholarly journals Normal Incidence of Diabetes in NOD Mice Tolerant to Glutamic Acid Decarboxylase

2003 ◽  
Vol 197 (12) ◽  
pp. 1635-1644 ◽  
Author(s):  
Elmar Jaeckel ◽  
Ludger Klein ◽  
Natalia Martin-Orozco ◽  
Harald von Boehmer
Keyword(s):  
Glutamic Acid ◽  
Glutamic Acid Decarboxylase ◽  
Tolerance Induction ◽  
Nod Mice ◽  
Normal Incidence ◽  
Invariant Chain ◽  
Acid Decarboxylase ◽  
Β Cells ◽  
Nonobese Diabetic ◽  
Specific Tolerance

Experiments in nonobese diabetic (NOD) mice that lacked expression of glutamic acid decarboxylase (GAD) in β cells have suggested that GAD represents an autoantigen essential for initiating and maintaining the diabetogenic immune response. Several attempts of inducing GAD-specific recessive tolerance to support this hypothesis have failed. Here we report on successful tolerance induction by expressing a modified form of GAD under control of the invariant chain promoter resulting in efficient epitope display. In spite of specific tolerance insulitis and diabetes occurred with normal kinetics indicating that GAD is not an essential autoantigen in the pathogenesis of diabetes.

Tolerogenic Delivery of a Hybrid Insulin Peptide Markedly Prolongs Islet Graft Survival in the Non-Obese Diabetic (NOD) Mouse

2022 ◽  
Author(s):  
Braxton L. Jamison ◽  
James E. DiLisio ◽  
K. Scott Beard ◽  
Tobias Neef ◽  
Brenda Bradley ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Survival ◽  
Tolerance Induction ◽  
Nod Mice ◽  
Disease Recurrence ◽  
Nod Mouse ◽  
Islet Graft ◽  
Specific Effector ◽  
Syngeneic Islet Transplantation ◽  
Specific Tolerance

The induction of antigen (Ag)-specific tolerance and replacement of islet β-cells are major ongoing goals for the treatment of Type 1 Diabetes (T1D). Our group previously showed that a hybrid insulin peptide (2.5HIP) is a critical autoantigen for diabetogenic CD4<sup>+</sup> T cells in the non-obese diabetic (NOD) mouse model. In this study, we investigated whether induction of Ag-specific tolerance using 2.5HIP-coupled tolerogenic nanoparticles (NPs) could protect diabetic NOD mice from disease recurrence upon syngeneic islet transplantation. Islet graft survival was significantly prolonged in mice treated with 2.5HIP NPs, but not NPs containing the insulin B chain peptide 9-23. Protection in 2.5HIP NP-treated mice was attributed both to the simultaneous induction of anergy in 2.5HIP-specific effector T cells and to the expansion of Foxp3+ regulatory T cells specific for the same antigen. Notably, our results indicate that effector function of graft-infiltrating CD4<sup>+</sup> and CD8<sup>+</sup> T cells specific for other β-cell epitopes was significantly impaired, suggesting a novel mechanism of therapeutically induced linked suppression. This work establishes that tolerance induction with a hybrid insulin peptide can delay recurrent autoimmunity in NOD mice, which could inform the development of an Ag-specific therapy for T1D.

scholarly journals A Human-Mouse Hybrid HLA-A2-IG Dimer Inhibits the Proliferation of CD4+T Cells In Vitro

2020 ◽  
Vol 1 (1) ◽  
pp. 8-14
Author(s):  
Victor Tunje Jeza ◽  
Chen Jun ◽  
Wu Xiongwen
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Nod Mice ◽  
Immunosuppressive Drugs ◽  
Major Drawback ◽  
Overlap Pcr ◽  
Donor Specific Tolerance ◽  
Specific Tolerance ◽  
Single Mismatch

Currently, general immunosuppressive drugs are used to maintain tolerance to allografts. However, these drugs have a major drawback of rendering the patient susceptible to infections and other side effects like malignancy and drug related toxicities with an overall rejection of the organ at some point. Previous studies have shown that MHC-Ig dimers may suppress alloresponsive T cells in a donor specific manner in vitro. This work aimed to answer the question as to whether these dimers will surmount rejection through the direct mechanism of allorecognition by suppressing alloreactive CD8+ T cells. To do this, we first identified two mice models with a single mismatch at the MHC loci. We found and procured white albino NOD mice which happened to be transgenic for HLA-A2 and HLA-A24 molecules. We then constructed a human-mouse hybrid HLA-A2-Ig dimer by overlap-PCR to join parts of two different already cloned plasmids to form the full length HLA-A2β2α1α2murineα3 insert which was then cloned to pcDNA3.1 to form pcDNA3.1HLA-A2β2α1α2murineα3. The IgG2bFc region was added by restriction digestion and ligation to form the plasmid pcDNA3.1HLA-A2β2α1α2murineα3IgG2bFc. Sequencing was done and confirmed that the construction and cloning were successful. The plasmid pcDNA3.1HLA-A2β2α1α2murineα3IgG2bFc was then transfected by electroporation to J558L cells. Screening was done using G418 for 4 weeks in cell culture. We purified the dimer by affinity chromatography and then used ELISA to confirm expression of the dimer. The purified dimer was then used in 1-way MLC experiments where responder cells were mice cells expressing HLA-A24 molecules while stimulator cells were mice cells expressing HLA-A2 molecules. Cell samples were gated on anti-mouse CD3-PE/CY7, anti-mouse CD4-PE, and anti-mouse CD8-APC/CY7. Cell proliferation was analysed using CFSE. Our results showed that the proliferation of CD4+ T cells was inhibited in the presence of the dimer. This work is crucial for subsequent studies aiming to search for induction of donor specific tolerance.

scholarly journals Tolerogenic Delivery of a Hybrid Insulin Peptide Markedly Prolongs Islet Graft Survival in the Non-Obese Diabetic (NOD) Mouse

2022 ◽  
Author(s):  
Braxton L. Jamison ◽  
James E. DiLisio ◽  
K. Scott Beard ◽  
Tobias Neef ◽  
Brenda Bradley ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Survival ◽  
Tolerance Induction ◽  
Nod Mice ◽  
Disease Recurrence ◽  
Nod Mouse ◽  
Islet Graft ◽  
Specific Effector ◽  
Syngeneic Islet Transplantation ◽  
Specific Tolerance

The induction of antigen (Ag)-specific tolerance and replacement of islet β-cells are major ongoing goals for the treatment of Type 1 Diabetes (T1D). Our group previously showed that a hybrid insulin peptide (2.5HIP) is a critical autoantigen for diabetogenic CD4<sup>+</sup> T cells in the non-obese diabetic (NOD) mouse model. In this study, we investigated whether induction of Ag-specific tolerance using 2.5HIP-coupled tolerogenic nanoparticles (NPs) could protect diabetic NOD mice from disease recurrence upon syngeneic islet transplantation. Islet graft survival was significantly prolonged in mice treated with 2.5HIP NPs, but not NPs containing the insulin B chain peptide 9-23. Protection in 2.5HIP NP-treated mice was attributed both to the simultaneous induction of anergy in 2.5HIP-specific effector T cells and to the expansion of Foxp3+ regulatory T cells specific for the same antigen. Notably, our results indicate that effector function of graft-infiltrating CD4<sup>+</sup> and CD8<sup>+</sup> T cells specific for other β-cell epitopes was significantly impaired, suggesting a novel mechanism of therapeutically induced linked suppression. This work establishes that tolerance induction with a hybrid insulin peptide can delay recurrent autoimmunity in NOD mice, which could inform the development of an Ag-specific therapy for T1D.

scholarly journals Induction of Antigen-Specific Tolerance in Autoimmune Diabetes with Nanoparticles Containing Hybrid Insulin Peptides

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 240
Author(s):  
James E. DiLisio ◽  
Kathryn Haskins
Keyword(s):  
T Cells ◽  
Autoimmune Diabetes ◽  
Tolerance Induction ◽  
Nod Mice ◽  
Cell Types ◽  
Dual Function ◽  
Transfer Model ◽  
Transplant Patients ◽  
Initial Work ◽  
Specific Tolerance

Autoreactive T cells are thought to orchestrate the onset and progression of autoimmune diabetes. Key cognate antigens of these diabetogenic T cells include hybrid insulin peptides, formed by the fusion of insulin fragments to cleavage products of other β-cell granule proteins. Here we review initial work exploring tolerance induction to a hybrid insulin peptide using a biodegradable, nanoparticle delivery system in non-obese diabetic (NOD) mice. The immune phenotype(s) and possible mechanism(s) behind antigen-specific tolerance induction were dissected with a disease transfer model using transgenic autoreactive mouse T cells. Treatment of NOD mice with peptide-coupled nanoparticles appeared to have a dual function in preventing diabetes onset, inducing anergy in effector T cells and enhancing the activity of regulatory T cells. Importantly, the ratio of these two cell types in the pancreas was pushed toward tolerance. Antigen-specific tolerance induction to hybrid insulin peptides has the translational potential to preserve islet β-cells in new-onset or at-risk patients and prevent recurrent autoimmunity in transplant patients.

scholarly journals Tolerogenic Delivery of a Hybrid Insulin Peptide Markedly Prolongs Islet Graft Survival in the Non-Obese Diabetic (NOD) Mouse

Diabetes ◽  
2022 ◽  
Author(s):  
Braxton L. Jamison ◽  
James E. DiLisio ◽  
K. Scott Beard ◽  
Tobias Neef ◽  
Brenda Bradley ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Survival ◽  
Tolerance Induction ◽  
Nod Mice ◽  
Disease Recurrence ◽  
Nod Mouse ◽  
Islet Graft ◽  
Specific Effector ◽  
Syngeneic Islet Transplantation ◽  
Specific Tolerance

The induction of antigen (Ag)-specific tolerance and replacement of islet β-cells are major ongoing goals for the treatment of Type 1 Diabetes (T1D). Our group previously showed that a hybrid insulin peptide (2.5HIP) is a critical autoantigen for diabetogenic CD4+ T cells in the non-obese diabetic (NOD) mouse model. In this study, we investigated whether induction of Ag-specific tolerance using 2.5HIP-coupled tolerogenic nanoparticles (NPs) could protect diabetic NOD mice from disease recurrence upon syngeneic islet transplantation. Islet graft survival was significantly prolonged in mice treated with 2.5HIP NPs, but not NPs containing the insulin B chain peptide 9-23. Protection in 2.5HIP NP-treated mice was attributed both to the simultaneous induction of anergy in 2.5HIP-specific effector T cells and to the expansion of Foxp3+ regulatory T cells specific for the same antigen. Notably, our results indicate that effector function of graft-infiltrating CD4+ and CD8+ T cells specific for other β-cell epitopes was significantly impaired, suggesting a novel mechanism of therapeutically induced linked suppression. This work establishes that tolerance induction with a hybrid insulin peptide can delay recurrent autoimmunity in NOD mice, which could inform the development of an Ag-specific therapy for T1D.

Total etch dentin bonding systems: scanning electron microscopy of the resin-dentin hybrid layer

1992 ◽  
Vol 50 (2) ◽  
pp. 1092-1093
Author(s):  
Jorge Perdigao
Keyword(s):  
Composite Resin ◽  
Mechanical Interlocking ◽  
Hybrid Layer ◽  
Agent Based ◽  
Dentin Bonding ◽  
Acid Agent ◽  
Bond Strengths ◽  
Main Component ◽  
Bonding Systems ◽  
New Generation

In 1955, Buonocore introduced the etching of enamel with phosphoric acid. Bonding to enamel was created by mechanical interlocking of resin tags with enamel prisms. Enamel is an inert tissue whose main component is hydroxyapatite (98% by weight). Conversely, dentin is a wet living tissue crossed by tubules containing cellular extensions of the dental pulp. Dentin consists of 18% of organic material, primarily collagen. Several generations of dentin bonding systems (DBS) have been studied in the last 20 years. The dentin bond strengths associated with these DBS have been constantly lower than the enamel bond strengths. Recently, a new generation of DBS has been described. They are applied in three steps: an acid agent on enamel and dentin (total etch technique), two mixed primers and a bonding agent based on a methacrylate resin. They are supposed to bond composite resin to wet dentin through dentin organic component, forming a peculiar blended structure that is part tooth and part resin: the hybrid layer.

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