Imaging the emergence and natural progression of spontaneous autoimmune diabetes

Type 1 diabetes in the nonobese diabetic mouse stems from an infiltration of the pancreatic islets by a mixed population of immunocytes, which results in the impairment and eventual destruction of insulin-producing β-cells. Little is known about the dynamics of lymphocyte movement in the pancreas during disease progression. Using advanced intravital imaging approaches and newly created reporter mice (Flt3-BFP2, Mertk-GFP-DTR, Cd4-tdTomato, Cd8a-tdTomato), we show that the autoimmune process initiates first with a T cell infiltration into the islets, where they have restricted mobility but reside and are activated in apposition to CX3CR1+ macrophages. The main expansion then occurs in the connective tissue outside the islet, which remains more or less intact. CD4+ and CD8+ T cells, Tregs, and dendritic cells (DCs) are highly mobile, going along microvascular tracks, while static macrophages (MF) form a more rigid structure, often encasing the islet cell mass. Transient cell–cell interactions are formed between T cells and both MFs and DCs, but also surprisingly between MFs and DCs themselves, possibly denoting antigen transfer. In later stages, extensive islet destruction coincides with preferential antigen presentation to, and activation of, CD8+ T cells. Throughout the process, Tregs patrol the active compartments, consistent with the notion that they control the activation of many cell types.

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T cell-mediated inhibition of the transfer of autoimmune diabetes in NOD mice.

Journal of Experimental Medicine ◽

10.1084/jem.169.5.1669 ◽

1989 ◽

Vol 169 (5) ◽

pp. 1669-1680 ◽

Cited By ~ 181

Author(s):

C Boitard ◽

R Yasunami ◽

M Dardenne ◽

J F Bach

Keyword(s):

T Cells ◽

Autoimmune Diabetes ◽

Nod Mice ◽

Insulin Dependent Diabetes Mellitus ◽

Lymphoid Cells ◽

Dependent Diabetes Mellitus ◽

Spleen Cells ◽

Nonobese Diabetic ◽

Insulin Dependent ◽

Onset Of Diabetes

The nonobese diabetic (NOD) mouse has recently been introduced as a model for insulin-dependent diabetes mellitus. The role of regulatory T cells in the development of antipancreatic autoimmunity in this model remains unclear. To evaluate the presence of suppressive phenomena, we used disease transfer by spleen cells from diabetic NOD mice into preirradiated adult recipients as a model for accelerated disease. Suppressor phenomena were detected by testing the protection afforded by lymphoid cells from nondiabetic NOD mice against diabetes transfer in irradiated recipients. Transfer of diabetes was delayed by reconstituting recipients with spleen cells from nondiabetic NOD donors. The greatest protection against diabetes transfer was conferred by spleen cells from 8-wk-old nondiabetic female NOD mice. Depletion experiments showed that the protection was dependent on CD4+ cells. Protection was also detected within thymic cells from nondiabetic NOD mice and protection conferred by spleen cells was abrogated by thymectomy of nondiabetic female, but not male, NOD donors at 3 wk of age. These findings indicate that suppressive CD4+ T cells that are dependent on the presence of the thymus may delay the onset of diabetes in female diabetes-prone NOD mice.

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Smad4 in T cells plays a protective role in the development of autoimmune Sjögren's syndrome in the nonobese diabetic mouse

Oncotarget ◽

10.18632/oncotarget.13437 ◽

2016 ◽

Vol 7 (49) ◽

pp. 80298-80312 ◽

Cited By ~ 2

Author(s):

Donghee Kim ◽

Jae Young Kim ◽

Hee-Sook Jun

Keyword(s):

T Cells ◽

Sjögren’S Syndrome ◽

Sjögren's Syndrome ◽

Sjogren’S Syndrome ◽

Diabetic Mouse ◽

Protective Role ◽

Sjogren's Syndrome ◽

Nonobese Diabetic Mouse ◽

Nonobese Diabetic ◽

Sjögren‘S Syndrome

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Reduced Incidence and Delayed Onset of Diabetes in Perforin-deficient Nonobese Diabetic Mice

Journal of Experimental Medicine ◽

10.1084/jem.186.7.989 ◽

1997 ◽

Vol 186 (7) ◽

pp. 989-997 ◽

Cited By ~ 160

Author(s):

David Kägi ◽

Bernhard Odermatt ◽

Peter Seiler ◽

Rolf M. Zinkernagel ◽

Tak W. Mak ◽

...

Keyword(s):

T Cells ◽

Autoimmune Diabetes ◽

Cytotoxic T Cells ◽

Disease Onset ◽

Spontaneous Diabetes ◽

Cell Loss ◽

Β Cell ◽

Nonobese Diabetic ◽

Nonobese Diabetic Mice ◽

Deficient Mice

To investigate the role of T cell–mediated, perforin-dependent cytotoxicity in autoimmune diabetes, perforin-deficient mice were backcrossed with the nonobese diabetes mouse strain. It was found that the incidence of spontaneous diabetes over a 1 yr period was reduced from 77% in perforin +/+ control to 16% in perforin-deficient mice. Also, the disease onset was markedly delayed (median onset of 39.5 versus 19 wk) in the latter. Insulitis with infiltration of CD4+ and CD8+ T cells occurred similarly in both groups of animals. Lower incidence and delayed disease onset were also evident in perforin-deficient mice when diabetes was induced by cyclophosphamide injection. Thus, perforin-dependent cytotoxicity is a crucial effector mechanism for β cell elimination by cytotoxic T cells in autoimmune diabetes. However, in the absence of perforin chronic inflammation of the islets can lead to diabetogenic β cell loss by less efficient secondary effector mechanisms.

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Differential effects of anti-B7-1 and anti-B7-2 monoclonal antibody treatment on the development of diabetes in the nonobese diabetic mouse.

Journal of Experimental Medicine ◽

10.1084/jem.181.3.1145 ◽

1995 ◽

Vol 181 (3) ◽

pp. 1145-1155 ◽

Cited By ~ 414

Author(s):

D J Lenschow ◽

S C Ho ◽

H Sattar ◽

L Rhee ◽

G Gray ◽

...

Keyword(s):

Monoclonal Antibody ◽

T Cells ◽

Autoimmune Diabetes ◽

Disease Process ◽

Nod Mice ◽

Dependent Diabetes Mellitus ◽

Antibody Treatment ◽

Treatment Groups ◽

Nonobese Diabetic ◽

Costimulatory Signals

Insulin-dependent diabetes mellitus (IDDM) is thought to be an immunologically mediated disease resulting in the complete destruction of the insulin-producing islets of Langerhans. It has become increasingly clear that autoreactive T cells play a major role in the development and progression of this disease. In this study, we examined the role of the CD28/B7 costimulation pathway in the development and progression of autoimmune diabetes in the nonobese diabetic (NOD) mouse model. Female NOD mice treated at the onset of insulitis (2-4 wk of age) with CTLA4Ig immunoglobulin (Ig) (a soluble CD28 antagonist) or a monoclonal antibody (mAb) specific for B7-2 (a CD28 ligand) did not develop diabetes. However, neither of these treatments altered the disease process when administered late, at > 10 wk of age. Histological examination of islets from the various treatment groups showed that while CTLA4Ig and anti-B7-2 mAb treatment blocked the development of diabetes, these reagents had little effect on the development or severity of insulitis. Together these results suggest that blockade of costimulatory signals by CTLA4Ig or anti-B7-2 acts early in disease development, after insulitis but before the onset of frank diabetes. NOD mice were also treated with mAbs to another CD28 ligand, B7-1. In contrast to the previous results, the anti-B7-1 treatment significantly accelerated the development of disease in female mice and, most interestingly, induced diabetes in normally resistant male mice. A combination of anti-B7-1 and anti-B7-2 mAbs also resulted in an accelerated onset of diabetes, similar to that observed with anti-B7-1 mAb treatment alone, suggesting that anti-B7-1 mAb's effect was dominant. Furthermore, treatment with anti-B7-1 mAbs resulted in a more rapid and severe infiltrate. Finally, T cells isolated from the pancreas of these anti-B7-1-treated animals exhibited a more activated phenotype than T cells isolated from any of the other treatment groups. These studies demonstrate that costimulatory signals play an important role in the autoimmune process, and that different members of the B7 family have distinct regulatory functions during the development of autoimmune diabetes.

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Local expression of transgene encoded TNF alpha in islets prevents autoimmune diabetes in nonobese diabetic (NOD) mice by preventing the development of auto-reactive islet-specific T cells.

Journal of Experimental Medicine ◽

10.1084/jem.184.5.1963 ◽

1996 ◽

Vol 184 (5) ◽

pp. 1963-1974 ◽

Cited By ~ 104

Author(s):

I S Grewal ◽

K D Grewal ◽

F S Wong ◽

D E Picarella ◽

C A Janeway ◽

...

Keyword(s):

T Cells ◽

Transgenic Mice ◽

Autoimmune Diabetes ◽

Nod Mice ◽

Lymphoid Cells ◽

Tnf Alpha ◽

Dependent Diabetes Mellitus ◽

Nonobese Diabetic ◽

Splenic Cells ◽

Local Expression

Lately, TNF alpha has been the focus of studies of autoimmunity; its role in the progression of autoimmune diabetes is, however, still unclear. To analyze the effects of TNF alpha in insulin-dependent diabetes mellitus (IDDM), we have generated nonobese diabetic (NOD) transgenic mice expressing TNF alpha under the control of the rat insulin II promoter (RIP). In transgenic mice, TNF alpha expression on the islets resulted in massive insulitis, composed of CD4+ T cells, CD8+ T cells, and B cells. Despite infiltration of considerable number of lymphoid cells in islets, expression of TNF alpha protected NOD mice from IDDM. To determine the mechanism of TNF alpha action, splenic cells from control NOD and RIP-TNF alpha mice were adoptively transferred to NOD-SCID recipients. In contrast to the induction of diabetes by splenic cells from control NOD mice, splenic cells from RIP-TNF alpha transgenic mice did not induce diabetes in NOD-SCID recipients. Diabetes was induced however, in the RIP-TNF alpha transgenic mice when CD8+ diabetogenic cloned T cells or splenic cells from diabetic NOD mice were adoptively transferred to these mice. Furthermore, expression of TNF alpha in islets also downregulated splenic cell responses to autoantigens. These data establish a mechanism of TNF alpha action and provide evidence that local expression of TNF alpha protects NOD mice from autoimmune diabetes by preventing the development of autoreactive islet-specific T cells.

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Overexpression of Bcl-2 in T Cells Affects Insulitis in the Nonobese Diabetic Mouse

Scandinavian Journal of Immunology ◽

10.1046/j.1365-3083.2003.01244.x ◽

2003 ◽

Vol 57 (4) ◽

pp. 342-349 ◽

Cited By ~ 5

Author(s):

C. Rietz ◽

V. Screpanti ◽

N. Brenden ◽

J. Bohme ◽

C. Fernandez

Keyword(s):

T Cells ◽

Diabetic Mouse ◽

Nonobese Diabetic Mouse ◽

Nonobese Diabetic

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The stromal cell–derived factor-1α/CXCR4 ligand–receptor axis is critical for progenitor survival and migration in the pancreas

The Journal of Cell Biology ◽

10.1083/jcb.200304153 ◽

2003 ◽

Vol 163 (4) ◽

pp. 859-869 ◽

Cited By ~ 76

Author(s):

Ayse G. Kayali ◽

Kurt Van Gunst ◽

Iain L. Campbell ◽

Aleksandr Stotland ◽

Marcie Kritzik ◽

...

Keyword(s):

Duct Cell ◽

Cell Types ◽

Diabetic Mouse ◽

Mitogen Activated Protein Kinase ◽

Ductal Cells ◽

Nonobese Diabetic ◽

Pancreatic Ductal Cells ◽

Stromal Cell Derived Factor ◽

And Migration ◽

Nonobese Diabetic Mice

The SDF-1α/CXCR4 ligand/chemokine receptor pair is required for appropriate patterning during ontogeny and stimulates the growth and differentiation of critical cell types. Here, we demonstrate SDF-1α and CXCR4 expression in fetal pancreas. We have found that SDF-1α and its receptor CXCR4 are expressed in islets, also CXCR4 is expressed in and around the proliferating duct epithelium of the regenerating pancreas of the interferon (IFN) γ–nonobese diabetic mouse. We show that SDF-1α stimulates the phosphorylation of Akt, mitogen-activated protein kinase, and Src in pancreatic duct cells. Furthermore, migration assays indicate a stimulatory effect of SDF-1α on ductal cell migration. Importantly, blocking the SDF-1α/CXCR4 axis in IFNγ-nonobese diabetic mice resulted in diminished proliferation and increased apoptosis in the pancreatic ductal cells. Together, these data indicate that the SDF-1α–CXCR4 ligand receptor axis is an obligatory component in the maintenance of duct cell survival, proliferation, and migration during pancreatic regeneration.

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