Expression of the B7.1 Costimulatory Molecule on Pancreatic β Cells Abrogates the Requirement for CD4 T Cells in the Development of Type 1 Diabetes

Type-1 diabetes mellitus (T1DM) is an autoimmune disease that has an impact on mortality due to the destruction of insulin-producing pancreatic β -cells in the islets of Langerhans. Over the past few years, the interest in analyzing this type of disease, either in a biological or mathematical sense, has relied on the search for a treatment that guarantees full control of glucose levels. Mathematical models inspired by natural phenomena, are proposed under the prey–predator scheme. T1DM fits in this scheme due to the complicated relationship between pancreatic β -cell population growth and leukocyte population growth via the immune response. In this scenario, β -cells represent the prey, and leukocytes the predator. This paper studies the global dynamics of T1DM reported by Magombedze et al. in 2010. This model describes the interaction of resting macrophages, activated macrophages, antigen cells, autolytic T-cells, and β -cells. Therefore, the localization of compact invariant sets is applied to provide a bounded positive invariant domain in which one can ensure that once the dynamics of the T1DM enter into this domain, they will remain bounded with a maximum and minimum value. Furthermore, we analyzed this model in a closed-loop scenario based on nonlinear control theory, and proposed bases for possible control inputs, complementing the model with them. These entries are based on the existing relationship between cell–cell interaction and the role that they play in the unchaining of a diabetic condition. The closed-loop analysis aims to give a deeper understanding of the impact of autolytic T-cells and the nature of the β -cell population interaction with the innate immune system response. This analysis strengthens the proposal, providing a system free of this illness—that is, a condition wherein the pancreatic β -cell population holds and there are no antigen cells labeled by the activated macrophages.

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Dextran Sulfate Protects Pancreatic β-Cells, Reduces Autoimmunity and Ameliorates Type 1 Diabetes

10.2337/figshare.12245363.v1 ◽

2020 ◽

Author(s):

Ada Admin ◽

Geming Lu ◽

Francisco Rausell-Palamos ◽

Jiamin Zhang ◽

Zihan Zheng ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Heparan Sulfate ◽

Dextran Sulfate ◽

Nod Mice ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells

A failure in self-tolerance leads to autoimmune destruction of pancreatic β-cells and type 1 diabetes (T1D). Low molecular weight dextran sulfate (DS) is a sulfated semi-synthetic polysaccharide with demonstrated cytoprotective and immunomodulatory properties in vitro. However, whether DS can protect pancreatic β-cells, reduce autoimmunity and ameliorate T1D is unknown. Here we report that DS, but not dextran, protects human β-cells against cytokine-mediated cytotoxicity in vitro. DS also protects mitochondrial function and glucose-stimulated insulin secretion and reduces chemokine expression in human islets in a pro-inflammatory environment. Interestingly, daily treatment with DS significantly reduces diabetes incidence in pre-diabetic non-obese diabetic (NOD) mice, and most importantly, reverses diabetes in early-onset diabetic NOD mice. DS decreases β-cell death, enhances islet heparan sulfate (HS)/heparan sulfate proteoglycan (HSPG) expression and preserves β-cell mass and plasma insulin in these mice. DS administration also increases the expression of the inhibitory co-stimulatory molecule programmed death-1 (PD-1) in T-cells, reduces interferon-γ+ CD4+ and CD8+ T-cells and enhances the number of FoxP3+ cells. Collectively, these studies demonstrate that the action of one single molecule, DS, on β-cell protection, extracellular matrix preservation and immunomodulation can reverse diabetes in NOD mice highlighting its therapeutic potential for the treatment of T1D.

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Dextran Sulfate Protects Pancreatic β-Cells, Reduces Autoimmunity and Ameliorates Type 1 Diabetes

10.2337/figshare.12245363 ◽

2020 ◽

Author(s):

Ada Admin ◽

Geming Lu ◽

Francisco Rausell-Palamos ◽

Jiamin Zhang ◽

Zihan Zheng ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Heparan Sulfate ◽

Dextran Sulfate ◽

Nod Mice ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells

A failure in self-tolerance leads to autoimmune destruction of pancreatic β-cells and type 1 diabetes (T1D). Low molecular weight dextran sulfate (DS) is a sulfated semi-synthetic polysaccharide with demonstrated cytoprotective and immunomodulatory properties in vitro. However, whether DS can protect pancreatic β-cells, reduce autoimmunity and ameliorate T1D is unknown. Here we report that DS, but not dextran, protects human β-cells against cytokine-mediated cytotoxicity in vitro. DS also protects mitochondrial function and glucose-stimulated insulin secretion and reduces chemokine expression in human islets in a pro-inflammatory environment. Interestingly, daily treatment with DS significantly reduces diabetes incidence in pre-diabetic non-obese diabetic (NOD) mice, and most importantly, reverses diabetes in early-onset diabetic NOD mice. DS decreases β-cell death, enhances islet heparan sulfate (HS)/heparan sulfate proteoglycan (HSPG) expression and preserves β-cell mass and plasma insulin in these mice. DS administration also increases the expression of the inhibitory co-stimulatory molecule programmed death-1 (PD-1) in T-cells, reduces interferon-γ+ CD4+ and CD8+ T-cells and enhances the number of FoxP3+ cells. Collectively, these studies demonstrate that the action of one single molecule, DS, on β-cell protection, extracellular matrix preservation and immunomodulation can reverse diabetes in NOD mice highlighting its therapeutic potential for the treatment of T1D.

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NK Cells and Type 1 Diabetes

Clinical and Developmental Immunology ◽

10.1080/17402520600877182 ◽

2006 ◽

Vol 13 (2-4) ◽

pp. 101-107 ◽

Cited By ~ 27

Author(s):

Melanie Rodacki ◽

Adolpho Milech ◽

José Egídio Paulo de Oliveira

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Nk Cells ◽

Target Cells ◽

Β Cells ◽

Pancreatic Β Cells ◽

Immune Mediated ◽

Antigen Presenting

Type 1 diabetes (T1D) is characterized by an immuno-mediated progressive destruction of the pancreatic β cells. Due to the ability of NK cells to kill target cells as well as to interact with antigen-presenting and T cells, it has been suggested that they could be involved in one or multiple steps of the immune-mediated attack that leads to T1D. Abnormalities in the frequency and activity of NK cells have been described both in animal models and patients with T1D. Some of these alterations are linked to its onset while others seem to be a consequence of the disease. Here, we discuss the main characteristics of NK cells and review the studies that investigated the role of NK cells in T1D, both in mouse models and humans.

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CD4 T cells can lyse islet β cells in type 1 diabetes

Journal of Autoimmunity ◽

10.1016/0896-8411(90)90046-u ◽

1990 ◽

Vol 3 (1) ◽

pp. 63

Author(s):

P. de Berardinis ◽

M. Londei ◽

R.F.L. James ◽

S.P. Lake ◽

M Feldmann

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Cd4 T Cells ◽

Β Cells

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Faculty Opinions recommendation of Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726147425.793514725 ◽

2016 ◽

Author(s):

David Serreze

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Cd4 T Cells

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Formation of pancreatic β-cells from precursor cells contributes to the reversal of established type 1 diabetes

Cellular Immunology ◽

10.1016/j.cellimm.2021.104360 ◽

2021 ◽

pp. 104360

Author(s):

Tobechukwu K. Ukah ◽

Alexis N. Cattin-Roy ◽

George E. Davis ◽

Habib Zaghouani

Keyword(s):

Type 1 Diabetes ◽

Precursor Cells ◽

Β Cells ◽

Pancreatic Β Cells

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Proinsulin-Reactive CD4 T Cells in the Islets of Type 1 Diabetes Organ Donors

Frontiers in Endocrinology ◽

10.3389/fendo.2021.622647 ◽

2021 ◽

Vol 12 ◽

Author(s):

Laurie G. Landry ◽

Amanda M. Anderson ◽

Holger A. Russ ◽

Liping Yu ◽

Sally C. Kent ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

T Cell ◽

Cd4 T Cells ◽

Pancreatic Beta Cells ◽

Hot Spot ◽

Cell Receptor ◽

Organ Donors ◽

Hla Dq

Proinsulin is an abundant protein that is selectively expressed by pancreatic beta cells and has been a focus for development of antigen-specific immunotherapies for type 1 diabetes (T1D). In this study, we sought to comprehensively evaluate reactivity to preproinsulin by CD4 T cells originally isolated from pancreatic islets of organ donors having T1D. We analyzed 187 T cell receptor (TCR) clonotypes expressed by CD4 T cells obtained from six T1D donors and determined their response to 99 truncated preproinsulin peptide pools, in the presence of autologous B cells. We identified 14 TCR clonotypes from four out of the six donors that responded to preproinsulin peptides. Epitopes were found across all of proinsulin (insulin B-chain, C-peptide, and A-chain) including four hot spot regions containing peptides commonly targeted by TCR clonotypes derived from multiple T1D donors. Of importance, these hot spots overlap with peptide regions to which CD4 T cell responses have previously been detected in the peripheral blood of T1D patients. The 14 TCR clonotypes recognized proinsulin peptides presented by various HLA class II molecules, but there was a trend for dominant restriction with HLA-DQ, especially T1D risk alleles DQ8, DQ2, and DQ8-trans. The characteristics of the tri-molecular complex including proinsulin peptide, HLA-DQ molecule, and TCR derived from CD4 T cells in islets, provides an essential basis for developing antigen-specific biomarkers as well as immunotherapies.

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