scholarly journals Adaptive Immunity and Pathogenesis of Diabetes: Insights Provided by the α4–Integrin Deficient NOD Mouse

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2597
Author(s):  
Salim Oulghazi ◽  
Sarah K. Wegner ◽  
Gabriele Spohn ◽  
Nina Müller ◽  
Sabine Harenkamp ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Islet Cell ◽  
Cell Injury ◽  
Nod Mice ◽  
Nod Mouse ◽  
Modest Contribution ◽  
Human Type 1 Diabetes

Background: The spontaneously diabetic “non-obese diabetic” (NOD) mouse is a faithful model of human type-1 diabetes (T1D). Methods: Given the pivotal role of α4 integrin (CD49d) in other autoimmune diseases, we generated NOD mice with α4-deficient hematopoiesis (NOD.α4-/-) to study the role of α4 integrin in T1D. Results: NOD.α4-/- mice developed islet-specific T-cells and antibodies, albeit quantitatively less than α4+ counterparts. Nevertheless, NOD.α4-/- mice were completely and life-long protected from diabetes and insulitis. Moreover, transplantation with isogeneic α4-/- bone marrow prevented progression to T1D of pre-diabetic NOD.α4+ mice despite significant pre-existing islet cell injury. Transfer of α4+/CD3+, but not α4+/CD4+ splenocytes from diabetic to NOD.α4-/- mice induced diabetes with short latency. Despite an only modest contribution of adoptively transferred α4+/CD3+ cells to peripheral blood, pancreas-infiltrating T-cells were exclusively graft derived, i.e., α4+. Microbiota of diabetes-resistant NOD.α4-/- and pre-diabetic NOD.α4+ mice were identical. Co- housed diabetic NOD.α4+ mice showed the characteristic diabetic dysbiosis, implying causality of diabetes for dysbiosis. Incidentally, NOD.α4-/- mice were protected from autoimmune sialitis. Conclusion: α4 is a potential target for primary or secondary prevention of T1D.

scholarly journals Development of Spontaneous Autoimmune Peripheral Polyneuropathy in B7-2–Deficient Nod Mice

2001 ◽  
Vol 194 (5) ◽  
pp. 677-684 ◽  
Author(s):  
Benoît Salomon ◽  
Lesley Rhee ◽  
Helene Bour-Jordan ◽  
Honor Hsin ◽  
Anthony Montag ◽  
...  
Keyword(s):  
T Cells ◽  
Nervous System ◽  
Autoimmune Diabetes ◽  
Chronic Inflammatory Demyelinating Polyneuropathy ◽  
Nod Mice ◽  
Nod Mouse ◽  
Nerve Tissue ◽  
Nonobese Diabetic ◽  
Peripheral Polyneuropathy

An increasing number of studies have documented the central role of T cell costimulation in autoimmunity. Here we show that the autoimmune diabetes-prone nonobese diabetic (NOD) mouse strain, deficient in B7-2 costimulation, is protected from diabetes but develops a spontaneous autoimmune peripheral polyneuropathy. All the female and one third of the male mice exhibited limb paralysis with histologic and electrophysiologic evidence of severe demyelination in the peripheral nerves beginning at 20 wk of age. No central nervous system lesions were apparent. The peripheral nerve tissue was infiltrated with dendritic cells, CD4+, and CD8+ T cells. Finally, CD4+ T cells isolated from affected animals induced the disease in NOD.SCID mice. Thus, the B7-2–deficient NOD mouse constitutes the first model of a spontaneous autoimmune disease of the peripheral nervous system, which has many similarities to the human disease, chronic inflammatory demyelinating polyneuropathy (CIDP). This model demonstrates that NOD mice have “cryptic” autoimmune defects that can polarize toward the nervous tissue after the selective disruption of CD28/B7-2 costimulatory pathway.

scholarly journals Identification of Candidate Tolerogenic CD8+T Cell Epitopes for Therapy of Type 1 Diabetes in the NOD Mouse Model

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Cailin Yu ◽  
Jeremy C. Burns ◽  
William H. Robinson ◽  
Paul J. Utz ◽  
Peggy P. Ho ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Nod Mice ◽  
Cell Protein ◽  
T Cell Epitopes ◽  
Predictive Algorithms ◽  
Murine Homolog ◽  
Human Type 1 Diabetes

Type 1 diabetes is an autoimmune disease in which insulin-producing pancreatic isletβcells are the target of self-reactive B and T cells. T cells reactive with epitopes derived from insulin and/or IGRP are critical for the initiation and maintenance of disease, but T cells reactive with other islet antigens likely have an essential role in disease progression. We sought to identify candidate CD8+T cell epitopes that are pathogenic in type 1 diabetes. Proteins that elicit autoantibodies in human type 1 diabetes were analyzed by predictive algorithms for candidate epitopes. Using several different tolerizing regimes using synthetic peptides, two new predicted tolerogenic CD8+T cell epitopes were identified in the murine homolog of the major human islet autoantigen zinc transporter ZnT8 (aa 158–166 and 282–290) and one in a non-βcell protein, dopamineβ-hydroxylase (aa 233–241). Tolerizing vaccination of NOD mice with a cDNA plasmid expressing full-length proinsulin prevented diabetes, whereas plasmids encoding ZnT8 and DβH did not. However, tolerizing vaccination of NOD mice with the proinsulin plasmid in combination with plasmids expressing ZnT8 and DβH decreased insulitis and enhanced prevention of disease compared to vaccination with the plasmid encoding proinsulin alone.

scholarly journals IFN Regulatory Factors 4 and 8 Expression in the NOD Mouse

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Gilles Besin ◽  
Simon Gaudreau ◽  
Émilie Dumont-Blanchette ◽  
Michael Ménard ◽  
Chantal Guindi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Type 1 Diabetes ◽  
Nod Mice ◽  
Nod Mouse ◽  
Dc Functions ◽  
Gm Csf ◽  
Diabetes Progression ◽  
Islet Inflammation

Dendritic cells (DCs) contribute to islet inflammation and its progression to diabetes in NOD mouse model and human. DCs play a crucial role in the presentation of autoantigen and activation of diabetogenic T cells, and IRF4 and IRF8 are crucial genes involved in the development of DCs. We have therefore investigated the expression of these genes in splenic DCs during diabetes progression in NOD mice. We found that IRF4 expression was upregulated in splenocytes and in splenic CD11c+DCs of NOD mice as compared to BALB/c mice. In contrast, IRF8 gene expression was higher in splenocytes of NOD mice whereas its expression was similar in splenic CD11c+DCs of NOD and BALB/c mice. Importantly, levels of IRF4 and IRF8 expression were lower in tolerogenic bone marrow derived DCs (BMDCs) generated with GM-CSF as compared to immunogenic BMDCs generated with GM-CSF and IL-4. Analysis of splenic DCs subsets indicated that high expression of IRF4 was associated with increased levels of CD4+CD8α−IRF4+CD11c+DCs but not CD4−CD8α+IRF8+CD11c+DCs in NOD mice. Our results showed that IRF4 expression was up-regulated in NOD mice and correlated with the increased levels of CD4+CD8α−DCs, suggesting that IRF4 may be involved in abnormal DC functions in type 1 diabetes in NOD mice.

scholarly journals New Insights Into the Role of Autoreactive CD8 T Cells and Cytokines in Human Type 1 Diabetes

2021 ◽  
Vol 11 ◽  
Author(s):  
Christine Bender ◽  
Sakthi Rajendran ◽  
Matthias G. von Herrath
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Beta Cell ◽  
Cd8 T Cells ◽  
Over Expression ◽  
Cell Dysfunction ◽  
Human Type ◽  
Human Type 1 Diabetes

Since the establishment of the network for pancreatic organ donors with diabetes (nPOD), we have gained unprecedented insight into the pathology of human type 1 diabetes. Many of the pre-existing “dogmas”, mostly derived from studies of animal models and sometimes limited human samples, have to be revised now. For example, we have learned that autoreactive CD8 T cells are present even in healthy individuals within the exocrine pancreas. Furthermore, their “attraction” to islets probably relies on beta-cell intrinsic events, such as the over-expression of MHC class I and resulting presentation of autoantigens such as (prepro)insulin. In addition, we are discovering other signs of beta-cell dysfunction, possibly at least in part due to stress, such as the over-expression of certain cytokines. This review summarizes the latest developments focusing on cytokines and autoreactive CD8 T cells in human type 1 diabetes pathogenesis.

scholarly journals IL-10 Deficiency Accelerates Type 1 Diabetes Development via Modulation of Innate and Adaptive Immune Cells and Gut Microbiota in BDC2.5 NOD Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Juan Huang ◽  
Qiyuan Tan ◽  
Ningwen Tai ◽  
James Alexander Pearson ◽  
Yangyang Li ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Gut Microbiota ◽  
Spontaneous Diabetes ◽  
Nod Mice ◽  
Treg Cells ◽  
Diabetes Development

Type 1 diabetes is an autoimmune disease caused by T cell-mediated destruction of insulin-producing β cells. BDC2.5 T cells in BDC2.5 CD4+ T cell receptor transgenic Non-Obese Diabetic (NOD) mice (BDC2.5+ NOD mice) can abruptly invade the pancreatic islets resulting in severe insulitis that progresses rapidly but rarely leads to spontaneous diabetes. This prevention of diabetes is mediated by T regulatory (Treg) cells in these mice. In this study, we investigated the role of interleukin 10 (IL-10) in the inhibition of diabetes in BDC2.5+ NOD mice by generating Il-10-deficient BDC2.5+ NOD mice (BDC2.5+Il-10-/- NOD mice). Our results showed that BDC2.5+Il-10-/- NOD mice displayed robust and accelerated diabetes development. Il-10 deficiency in BDC2.5+ NOD mice promoted the generation of neutrophils in the bone marrow and increased the proportions of neutrophils in the periphery (blood, spleen, and islets), accompanied by altered intestinal immunity and gut microbiota composition. In vitro studies showed that the gut microbiota from BDC2.5+Il-10-/- NOD mice can expand neutrophil populations. Moreover, in vivo studies demonstrated that the depletion of endogenous gut microbiota by antibiotic treatment decreased the proportion of neutrophils. Although Il-10 deficiency in BDC2.5+ NOD mice had no obvious effects on the proportion and function of Treg cells, it affected the immune response and activation of CD4+ T cells. Moreover, the pathogenicity of CD4+ T cells was much increased, and this significantly accelerated the development of diabetes when these CD4+ T cells were transferred into immune-deficient NOD mice. Our study provides novel insights into the role of IL-10 in the modulation of neutrophils and CD4+ T cells in BDC2.5+ NOD mice, and suggests important crosstalk between gut microbiota and neutrophils in type 1 diabetes development.

scholarly journals Tet2 Controls the Responses of β cells to Inflammation in Autoimmune Diabetes

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jinxiu Rui ◽  
Songyan Deng ◽  
Ana Luisa Perdigoto ◽  
Gerald Ponath ◽  
Romy Kursawe ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Type 1 Diabetes ◽  
Immune Cells ◽  
Autoimmune Diabetes ◽  
Bone Marrow Transplants ◽  
Β Cells ◽  
Inflammatory Genes

Abstractβ cells may participate and contribute to their own demise during Type 1 diabetes (T1D). Here we report a role of their expression of Tet2 in regulating immune killing. Tet2 is induced in murine and human β cells with inflammation but its expression is reduced in surviving β cells. Tet2-KO mice that receive WT bone marrow transplants develop insulitis but not diabetes and islet infiltrates do not eliminate β cells even though immune cells from the mice can transfer diabetes to NOD/scid recipients. Tet2-KO recipients are protected from transfer of disease by diabetogenic immune cells.Tet2-KO β cells show reduced expression of IFNγ-induced inflammatory genes that are needed to activate diabetogenic T cells. Here we show that Tet2 regulates pathologic interactions between β cells and immune cells and controls damaging inflammatory pathways. Our data suggests that eliminating TET2 in β cells may reduce activating pathologic immune cells and killing of β cells.

Regeneration of insulin-producing [beta]-cells during recovery from disease: a cure for Type 1 Diabetes

2018 ◽  
Author(s):  
◽  
Tobechukwu Kenneth Ukah
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Combination Therapy ◽  
Beta Cells ◽  
Th17 Cells ◽  
Nod Mice ◽  
I Cells

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Type 1 diabetes (T1D) is a chronic disease condition characterized by destruction of the insulin-producing [beta]-cells by self-reactive lymphocytes of the immune system. While some immunotherapeutic approaches against T1D directly target and modulate diabetogenic specific T cells or the entire T cell repertoire, other efforts utilize antigen presenting cells or T cell-regulating molecules to control the T cells. In chapter II, we set out to determine the role of regulatory cytokines, IL-4 and IL-13 in T1D progression. IL-4 and IL-13 are widely reported as anti-inflammatory cytokines, and both can signal via the IL-4R[alpha]/IL-13R[alpha]1 heteroreceptor (HR). To determine the role of these cytokines in T1D development, we generated NOD mice in which the IL-13R[alpha]1 arm of the HR is deleted, thereby rendering the HR nonfunctional. Surprisingly, the findings indicate that NOD mice lacking the HR (13R-/-) display resistance to T1D as the rise in blood glucose level (BGL) and islet inflammation were significantly delayed in these HR-deficient relative to HR-sufficient (13R+/+) mice. In fact, the frequency and spleen-to-pancreas dynamics of both Th1 and Th17 cells were affected in 13R-/- mice. This outcome is likely due to an increase in the frequency of mTGF[beta][subscript +]Foxp3[subscript int] regulatory T cells and persistence of CD206[subscript +] macrophage in the pancreas as both types of cells confer resistance to T1D upon transfer to 13R+/+ mice. These findings reveal new insights as to the role environmental IL-4/IL-13 and the HR play in peripheral tolerance and the development of T1D. In chapter III, we investigate the source of newly formed β-cells during recovery from overt T1D under a combination therapy that involves an immunoglobulin chimera, Ig-GAD2 and bone marrow cells transfer. This combination therapy proved effective in driving immune modulation of diabetogenic-specific T cells and repair of the islet vasculature leading to the formation of new endogenous [beta]-cells that were able to thrive and restore long-lasting normoglycemia. Our new findings reveal and suggest that the combination therapy leads to the formation of healthy islets by inducing division of residual β-cells and differentiation of precursor cells. Furthermore, while the pancreas is cleared of immune infiltration during recovery from disease, both the lymph nodes and spleen displayed a significant reduction in Th17 cells, and the disease did not rebound. These circumstances are relevant to humans as intervention could be made at early as well as late stages after diagnosis. Overall, these results provide insights on future immunotherapeutic measures of T1D using regulatory cytokines or intervention with an antigen-specific therapy.

scholarly journals Identification and characterisation of tertiary lymphoid organs in human type 1 diabetes

Diabetologia ◽  
2021 ◽  
Author(s):  
Éva Korpos ◽  
Nadir Kadri ◽  
Sophie Loismann ◽  
Clais R. Findeisen ◽  
Frank Arfuso ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Disease Duration ◽  
Nod Mice ◽  
Nod Mouse ◽  
Islet Autoimmunity ◽  
Clinical Settings ◽  
Human Type ◽  
Human Type 1 Diabetes

Abstract Aims/hypothesis We and others previously reported the presence of tertiary lymphoid organs (TLOs) in the pancreas of NOD mice, where they play a role in the development of type 1 diabetes. Our aims here are to investigate whether TLOs are present in the pancreas of individuals with type 1 diabetes and to characterise their distinctive features, in comparison with TLOs present in NOD mouse pancreases, in order to interpret their functional significance. Methods Using immunofluorescence confocal microscopy, we examined the extracellular matrix (ECM) and cellular constituents of pancreatic TLOs from individuals with ongoing islet autoimmunity in three distinct clinical settings of type 1 diabetes: at risk of diabetes; at/after diagnosis; and in the transplanted pancreas with recurrent diabetes. Comparisons were made with TLOs from 14-week-old NOD mice, which contain islets exhibiting mild to heavy leucocyte infiltration. We determined the frequency of the TLOs in human type 1diabetes with insulitis and investigated the presence of TLOs in relation to age of onset, disease duration and disease severity. Results TLOs were identified in preclinical and clinical settings of human type 1 diabetes. The main characteristics of these TLOs, including the cellular and ECM composition of reticular fibres (RFs), the presence of high endothelial venules and immune cell subtypes detected, were similar to those observed for TLOs from NOD mouse pancreases. Among 21 donors with clinical type 1 diabetes who exhibited insulitis, 12 had TLOs and had developed disease at younger age compared with those lacking TLOs. Compartmentalised TLOs with distinct T cell and B cell zones were detected in donors with short disease duration. Overall, TLOs were mainly associated with insulin-containing islets and their frequency decreased with increasing severity of beta cell loss. Parallel studies in NOD mice further revealed some differences in so far as regulatory T cells were essentially absent from human pancreatic TLOs and CCL21 was not associated with RFs. Conclusions/interpretation We demonstrate a novel feature of pancreas pathology in type 1 diabetes. TLOs represent a potential site of autoreactive effector T cell generation in islet autoimmunity and our data from mouse and human tissues suggest that they disappear once the destructive process has run its course. Thus, TLOs may be important for type 1 diabetes progression. Graphical abstract

The Role of Human T-Lymphotropic Virus Type 1 (HTLV-1)-Infected Dendritic Cells in the Development of HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis

1999 ◽  
Vol 73 (6) ◽  
pp. 4575-4581 ◽  
Author(s):  
Masahiko Makino ◽  
Satoshi Shimokubo ◽  
Shin-Ichi Wakamatsu ◽  
Shuji Izumo ◽  
Masanori Baba
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Virus Type ◽  
Spastic Paraparesis ◽  
Tropical Spastic Paraparesis ◽  
Normal Donor ◽  
Dependent Manner ◽  
T Lymphotropic Virus

ABSTRACT The development of human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is closely associated with the activation of T cells which are HTLV-1 specific but may cross-react with neural antigens (Ags). Immature dendritic cells (DCs), differentiated from normal donor monocytes by using recombinant granulocyte-macrophage colony-stimulating factor and recombinant interleukin-4, were pulsed with HTLV-1 in vitro. The pulsed DCs contained HTLV-1 proviral DNA and expressed HTLV-1 Gag Ag on their surface 6 days after infection. The DCs matured by lipopolysaccharides stimulated autologous CD4+ T cells and CD8+ T cells in a viral dose-dependent manner. However, the proliferation level of CD4+ T cells was five- to sixfold higher than that of CD8+ T cells. In contrast to virus-infected DCs, DCs pulsed with heat-inactivated virions activated only CD4+ T cells. To clarify the role of DCs in HAM/TSP development, monocytes from patients were cultured for 4 days in the presence of the cytokines. The expression of CD86 Ag on DCs was higher and that of CD1a Ag was more down-regulated than in DCs generated from normal monocytes. DCs from two of five patients expressed HTLV-1 Gag Ag. Furthermore, both CD4+ and CD8+ T cells from the patients were greatly stimulated by contact with autologous DCs pulsed with inactivated viral Ag as well as HTLV-1-infected DCs. These results suggest that DCs are susceptible to HTLV-1 infection and that their cognate interaction with T cells may contribute to the development of HAM/TSP.

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