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

Author(s):  
Braxton L. Jamison ◽  
James E. DiLisio ◽  
K. Scott Beard ◽  
Tobias Neef ◽  
Brenda Bradley ◽  
...  

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.

2022 ◽  
Author(s):  
Braxton L. Jamison ◽  
James E. DiLisio ◽  
K. Scott Beard ◽  
Tobias Neef ◽  
Brenda Bradley ◽  
...  

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.


Diabetes ◽  
2022 ◽  
Author(s):  
Braxton L. Jamison ◽  
James E. DiLisio ◽  
K. Scott Beard ◽  
Tobias Neef ◽  
Brenda Bradley ◽  
...  

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.


Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 240
Author(s):  
James E. DiLisio ◽  
Kathryn Haskins

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.


2012 ◽  
Vol 12 (5) ◽  
pp. 1124-1132 ◽  
Author(s):  
Q. Shi ◽  
J. R. Lees ◽  
D. W. Scott ◽  
D. L. Farber ◽  
S. T. Bartlett

2003 ◽  
Vol 197 (12) ◽  
pp. 1635-1644 ◽  
Author(s):  
Elmar Jaeckel ◽  
Ludger Klein ◽  
Natalia Martin-Orozco ◽  
Harald von Boehmer

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.


2009 ◽  
Vol 47 (3) ◽  
pp. 284-292 ◽  
Author(s):  
Gu-Jiun Lin ◽  
Shing-Hwa Huang ◽  
Yuan-Wu Chen ◽  
Dueng-Yuan Hueng ◽  
Ming-Wei Chien ◽  
...  
Keyword(s):  
Nod Mice ◽  

Diabetes ◽  
2004 ◽  
Vol 53 (9) ◽  
pp. 2338-2345 ◽  
Author(s):  
Q. Shi ◽  
D. Wang ◽  
G. A. Hadley ◽  
A. W. Bingaman ◽  
S. T. Bartlett ◽  
...  
Keyword(s):  
Nod Mice ◽  

2011 ◽  
Vol 71 (1) ◽  
pp. 120-128 ◽  
Author(s):  
Honorio Torres-Aguilar ◽  
Miri Blank ◽  
Shaye Kivity ◽  
Mudi Misgav ◽  
Jacob Luboshitz ◽  
...  

ObjectivesThe importance of β2-glycoprotein I (β2GPI)-specific CD4+ T cells in the development of pathogenic processes in patients with antiphospholipid syndrome (APS) and APS mouse models is well established. Therefore, our objective is to manipulate the β2GPI specific CD4+ T cells using tolerogenic dendritic cells (tDCs) to induce tolerance. We aim to evaluate the capability of tDCs to induce antigen-specific tolerance in effector/memory T cells from patients with APS and to elucidate the involved mechanism.MethodsDCs and tDCs were produced from patients with APS peripheral-blood-monocytes, using specific cytokines. β2GPI-specific tolerance induction was investigated by coculturing control DC (cDC) or tDC, β2GPI-loaded, with autologous effector/memory T cells, evaluating the proliferative response, phenotype, cytokines secretion, viability and regulatory T cells.ResultsHuman monocyte-derived DCs treated with interleukin (IL)-10 and transforming growth factor β-1 (10/TGF-DC) induced β2GPI-specific-unresponsiveness in effector/memory CD4+ T cells (46.5%±26.0 less proliferation) in 16 of 20 analysed patients with APS, without affecting the proliferative response to an unrelated candidin. In five analysed patients, 10/TGF-DC-stimulated T cells acquired an IL-2lowinterferon γlowIL-10high cytokine profile, with just a propensity to express higher numbers of Foxp3+CTLA-4+ cells, but with an evident suppressive ability. In four of 10 analysed patients, 10/TGF-DC-stimulated T cell hyporesponsiveness could not be reverted and showed higher percentages of late apoptosis, p<0.02.ConclusionsThe inherent tolerance induction resistance of activated T cells present during the development of autoimmune diseases has delayed the application of tDC as an alternative therapy. This study highlights the 10/TGF-DC feasibility to induce antigen-specific unresponsiveness in autoreactive T cells generated in patients with APS by inducing apoptosis or T cells with regulatory abilities.


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