scholarly journals Pancreatic Lymph Nodes Are Required for Priming of β Cell Reactive T Cells in NOD Mice

2002 ◽  
Vol 196 (3) ◽  
pp. 369-377 ◽  
Author(s):  
Marie-Claude Gagnerault ◽  
Jian Jian Luan ◽  
Chantal Lotton ◽  
Françoise Lepault
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
Autoimmune Diabetes ◽  
Adult Life ◽  
Nod Mice ◽  
Autoreactive T Cells ◽  
Nonobese Diabetic ◽  
Autoreactive T Cell ◽  
Pancreatic Lymph Nodes ◽  
Diabetes Development

Nonobese diabetic (NOD) mice develop spontaneous autoimmune diabetes that results from the destruction of insulin secreting β cells by diabetogenic T cells. The time and location of the encounter of autoantigen(s) by naive autoreactive T cells in normal NOD mice are still elusive. To address these issues, we analyzed diabetes development in mice whose spleen or pancreatic lymph nodes (panLNs) had been removed. Excision of panLNs (panLNx) at 3 wk protected mice against insulin autoantibodies (IAAs), insulitis, and diabetes development almost completely, but had no effect when performed at 10 wk. The protection afforded by panLNx at weaning was not due to modifications of the immune system, the absence of autoreactive T cells, or the increase in the potency of regulatory T cells. That panLNs are dispensable during adult life was confirmed by the capacity of 10-wk-old panLNx irradiated recipients to develop diabetes upon transfer of diabetogenic T cells. In contrast, splenectomy had no effect at any age. Partial excision of mesenteric LN at 3 wk did not prevent accelerated diabetes by cyclophosphamide as panLNx did. Thus, in normal NOD mice, autoreactive T cell initial priming occurs in LNs draining the target organ of the disease from 3 wk of age.

Protection against autoimmune diabetes with oral insulin is associated with the presence of IL-4 type 2 T-cells in the pancreas and pancreatic lymph nodes

Diabetes ◽  
1998 ◽  
Vol 47 (1) ◽  
pp. 39-44 ◽  
Author(s):  
C. Ploix ◽  
I. Bergerot ◽  
N. Fabien ◽  
S. Perche ◽  
V. Moulin ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
Autoimmune Diabetes ◽  
Oral Insulin ◽  
Pancreatic Lymph Nodes

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

1989 ◽  
Vol 169 (5) ◽  
pp. 1669-1680 ◽  
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.

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

1995 ◽  
Vol 181 (3) ◽  
pp. 1145-1155 ◽  
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.

scholarly journals 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.

1996 ◽  
Vol 184 (5) ◽  
pp. 1963-1974 ◽  
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.

scholarly journals Initiation of Autoimmune Diabetes by Developmentally Regulated Presentation of Islet Cell Antigens in the Pancreatic Lymph Nodes

1999 ◽  
Vol 189 (2) ◽  
pp. 331-339 ◽  
Author(s):  
Petter Höglund ◽  
Justine Mintern ◽  
Caroline Waltzinger ◽  
William Heath ◽  
Christophe Benoist ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Beta Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Molecular Mimicry ◽  
Autoimmune Diabetes ◽  
Activated T Cells ◽  
Pancreatic Lymph Nodes

Little is known about the events triggering lymphocyte invasion of the pancreatic islets in prelude to autoimmune diabetes. For example, where islet-reactive T cells first encounter antigen has not been identified. We addressed this issue using BDC2.5 T cell receptor transgenic mice, which express a receptor recognizing a natural islet beta cell antigen. In BDC2.5 animals, activated T cells were found only in the islets and the lymph nodes draining them, and there was a close temporal correlation between lymph node T cell activation and islet infiltration. When naive BDC2.5 T cells were transferred into nontransgenic recipients, proliferating cells were observed only in pancreatic lymph nodes, and this occurred significantly before insulitis was detectable. Surprisingly, proliferation was not seen in 10-day-old recipients. This age-dependent dichotomy was reproduced in a second transfer system based on an unrelated antigen artificially expressed on beta cells. We conclude that beta cell antigens are transported specifically to pancreatic lymph nodes, where they trigger reactive T cells to invade the islets. Systemic or extrapancreatic T cell priming, indicative of activation via molecular mimicry or superantigens, was not seen. Compromised presentation of beta cell antigens in the pancreatic lymph nodes of juvenile animals may be the root of a first “checkpoint” in diabetes progression.

scholarly journals Dendritic cell–expanded, islet-specific CD4+ CD25+ CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice

2007 ◽  
Vol 204 (1) ◽  
pp. 191-201 ◽  
Author(s):  
Kristin V. Tarbell ◽  
Lucine Petit ◽  
Xiaopan Zuo ◽  
Priscilla Toy ◽  
Xunrong Luo ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cell ◽  
Regulatory T Cells ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Cell Receptor ◽  
Suppressor T Cells ◽  
Nonobese Diabetic ◽  
Glucose Challenge ◽  
Infiltrating Lymphocytes

Most treatments that prevent autoimmune diabetes in nonobese diabetic (NOD) mice require intervention at early pathogenic stages, when insulitis is first developing. We tested whether dendritic cell (DC)–expanded, islet antigen–specific CD4+ CD25+ suppressor T cells could treat diabetes at later stages of disease, when most of the insulin-producing islet β cells had been destroyed by infiltrating lymphocytes. CD4+ CD25+ CD62L+ regulatory T cells (T reg cells) from BDC2.5 T cell receptor transgenic mice were expanded with antigen-pulsed DCs and IL-2, and were then injected into NOD mice. A single dose of as few as 5 × 104 of these islet-specific T reg cells blocked diabetes development in prediabetic 13-wk-old NOD mice. The T reg cells also induced long-lasting reversal of hyperglycemia in 50% of mice in which overt diabetes had developed. Successfully treated diabetic mice had similar responses to glucose challenge compared with nondiabetic NOD mice. The successfully treated mice retained diabetogenic T cells, but also had substantially increased Foxp3+ cells in draining pancreatic lymph nodes. However, these Foxp3+ cells were derived from the recipient mice and not the injected T reg cells, suggesting a role for endogenous T reg cells in maintaining tolerance after treatment. Therefore, inoculation of DC-expanded, antigen-specific suppressor T cells has considerable efficacy in ameliorating ongoing diabetes in NOD mice.

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