scholarly journals Reversal of Spontaneous Autoimmune Insulitis in Nonobese Diabetic Mice by Soluble Lymphotoxin Receptor

2001 ◽  
Vol 193 (11) ◽  
pp. 1327-1332 ◽  
Author(s):  
Qiang Wu ◽  
Benoît Salomon ◽  
Min Chen ◽  
Yang Wang ◽  
Lisa M. Hoffman ◽  
...  
Keyword(s):  
Autoimmune Diabetes ◽  
Critical Role ◽  
Insulin Dependent Diabetes Mellitus ◽  
Dependent Diabetes Mellitus ◽  
Transfer Model ◽  
Diabetic Mice ◽  
Nonobese Diabetic ◽  
Insulin Dependent ◽  
Nonobese Diabetic Mice

One striking feature of spontaneous autoimmune diabetes is the prototypic formation of lymphoid follicular structures within the pancreas. Lymphotoxin (LT) has been shown to play an important role in the formation of lymphoid follicles in the spleen. To explore the potential role of LT-mediated microenvironment in the pathogenesis of insulin-dependent diabetes mellitus (IDDM), an LTβ receptor–immunoglobulin fusion protein (LTβR–Ig) was administered to nonobese diabetic mice. Early treatment with LTβR–Ig prevented insulitis and IDDM, suggesting that LT plays a critical role in the insulitis development. LTβR–Ig treatment at a late stage of the disease also dramatically reversed insulitis and prevented diabetes. Moreover, LTβR–Ig treatment prevented the development of IDDM by diabetogenic T cells in an adoptive transfer model. Thus, LTβR–Ig can disassemble the well established lymphoid microenvironment in the islets, which is required for the development and progression of IDDM.

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 Requirement of Fas for the Development of Autoimmune Diabetes in Nonobese Diabetic Mice

1997 ◽  
Vol 186 (4) ◽  
pp. 613-618 ◽  
Author(s):  
Naoto Itoh ◽  
Akihisa Imagawa ◽  
Toshiaki Hanafusa ◽  
Masako Waguri ◽  
Koji Yamamoto ◽  
...  
Keyword(s):  
Fas Ligand ◽  
Autoimmune Diabetes ◽  
Spontaneous Diabetes ◽  
Nod Mice ◽  
Insulin Dependent Diabetes Mellitus ◽  
Dependent Diabetes Mellitus ◽  
Β Cell ◽  
Cell Destruction ◽  
Nonobese Diabetic

Insulin-dependent diabetes mellitus (IDDM) is assumed to be a T cell–mediated autoimmune disease. To investigate the role of Fas-mediated cytotoxicity in pancreatic β cell destruction, we established nonobese diabetic (NOD)-lymphoproliferation (lpr)/lpr mice lacking Fas. Out of three genotypes, female NOD-+/+ and NOD-+/lpr developed spontaneous diabetes by the age of 10 mo with the incidence of 68 and 62%, respectively. In contrast, NOD-lpr/lpr did not develop diabetes or insulitis. To further explore the role of Fas, adoptive transfer experiments were performed. When splenocytes were transferred from diabetic NOD, male NOD-+/+ and NOD-+/lpr developed diabetes with the incidence of 89 and 83%, respectively, whereas NOD-lpr/lpr did not show glycosuria by 12 wk after transfer. Severe mononuclear cell infiltration was revealed in islets of NOD-+/+ and NOD-+/lpr, whereas islet morphology remained intact in NOD-lpr/lpr. These results suggest that Fas-mediated cytotoxicity is required to initiate β cell autoimmunity in NOD mice. Fas–Fas ligand system might be critical for autoimmune β cell destruction leading to IDDM.

scholarly journals A predominant role of integrin alpha 4 in the spontaneous development of autoimmune diabetes in nonobese diabetic mice.

1994 ◽  
Vol 91 (26) ◽  
pp. 12604-12608 ◽  
Author(s):  
X. D. Yang ◽  
S. A. Michie ◽  
R. Tisch ◽  
N. Karin ◽  
L. Steinman ◽  
...  
Keyword(s):  
Autoimmune Diabetes ◽  
Diabetic Mice ◽  
Predominant Role ◽  
Nonobese Diabetic ◽  
Nonobese Diabetic Mice

scholarly journals Production of interleukin 10 by islet cells accelerates immune-mediated destruction of beta cells in nonobese diabetic mice.

1994 ◽  
Vol 179 (4) ◽  
pp. 1379-1384 ◽  
Author(s):  
L Wogensen ◽  
M S Lee ◽  
N Sarvetnick
Keyword(s):  
Islet Cells ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Insulin Dependent Diabetes Mellitus ◽  
Interleukin 10 ◽  
Diabetic Mouse ◽  
Dependent Diabetes Mellitus ◽  
Beta Cell Destruction ◽  
Nonobese Diabetic ◽  
Nonobese Diabetic Mice

The T helper type 2 (Th2) cell product interleukin 10 (IL-10) inhibits the proliferation and function of Th1 lymphocytes and macrophages (M phi). The nonobese diabetic mouse strain (NOD/Shi) develops a M phi and T cell-dependent autoimmune diabetes that closely resembles human insulin-dependent diabetes mellitus (IDDM). The objective of the present study was to explore the consequences of localized production of IL-10 on diabetes development in NOD/Shi mice. Surprisingly, local production of IL-10 accelerated the onset and increased the prevalence of diabetes, since diabetes developed at 5-10 wk of age in 92% of IL-10 positive I-A beta g7/g7, I-E- mice in first (N2) and second (N3) generation backcrosses between IL-10 transgenic BALB/c mice and (NOD/Shi) mice. None of the IL-10 negative major histocompatibility complex-identical littermates were diabetic at this age. Furthermore, diabetes developed in 33% of I-A beta g7/d, I-E+ N3 mice in the presence of IL-10 before the mice were 10 wk old. Our findings support the notion that IL-10 should not simply be regarded as an immunoinhibitory cytokine, since it possesses powerful, immunostimulatory properties as well. Furthermore, our observations suggest that beta cell destruction in NOD mice may be a Th2-mediated event.

scholarly journals Cd1-Restricted Nk T Cells Protect Nonobese Diabetic Mice from Developing Diabetes

2001 ◽  
Vol 194 (3) ◽  
pp. 313-320 ◽  
Author(s):  
Bin Wang ◽  
Yan-Biao Geng ◽  
Chyung-Ru Wang
Keyword(s):  
T Cells ◽  
Autoimmune Diseases ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Insulin Dependent Diabetes Mellitus ◽  
Dependent Diabetes Mellitus ◽  
Dependent Manner ◽  
Nonobese Diabetic ◽  
Nk T Cells

NK T cells are a unique subset of T cells that recognize lipid antigens presented by CD1d. After activation, NK T cells promptly produce large amounts of cytokines, which may modulate the upcoming immune responses. Previous studies have documented an association between decreased numbers of NK T cells and the progression of some autoimmune diseases, suggesting that NK T cells may control the development of autoimmune diseases. To investigate the role of NK T cells in autoimmune diabetes, we crossed CD1 knockout (CD1KO) mutation onto the nonobese diabetic (NOD) genetic background. We found that male CD1KO NOD mice exhibited significantly higher incidence and earlier onset of diabetes compared with the heterozygous controls. The diabetic frequencies in female mice showed a similar pattern; however, the differences were less profound between female CD1KO and control mice. Early treatment of NOD mice with α-galactosylceramide, a potent NK T cell activator, reduced the severity of autoimmune diabetes in a CD1-dependent manner. Our results not only suggest a protective role of CD1-restricted NK T cells in autoimmune diabetes but also reveal a causative link between the deficiency of NK T cells and the induction of insulin-dependent diabetes mellitus.

scholarly journals CD4+ beta islet cell-reactive T cell clones that suppress autoimmune diabetes in nonobese diabetic mice.

1995 ◽  
Vol 182 (1) ◽  
pp. 87-97 ◽  
Author(s):  
I Akhtar ◽  
J P Gold ◽  
L Y Pan ◽  
J L Ferrara ◽  
X D Yang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Islet Cell ◽  
Insulin Dependent Diabetes Mellitus ◽  
Dependent Diabetes Mellitus ◽  
T Cell Clones ◽  
Nonobese Diabetic ◽  
Cell Clones ◽  
Insulin Dependent ◽  
Nonobese Diabetic Mice

We report the isolation of a panel of CD4+ T helper type 1 autoreactive T cell clones from the spleen of unprimed nonobese diabetic mice, a murine model of human insulin-dependent diabetes mellitus. The T cell clones express a diverse repertoire of T cell receptors, three of which recognize beta islet cell autoantigen(s). The islet cell-reactive T cell clones inhibit adoptive transfer of insulin-dependent diabetes mellitus and intraislet lymphocytic infiltration. The protective capacity of the T cell clones correlates with their ability to produce a novel immunoregulatory activity that potently inhibits in vitro allogeneic mixed lymphocyte reaction. The partially purified activity significantly inhibited the adoptive transfer of diabetes. Our work provides evidence in support of the existence of T helper type 1, CD4+ T cells reactive to beta islet cell autoantigens that have acquired a protective instead of a diabetogenic effector function. These T cells mediate their protective action in part by production of an immunoregulatory activity capable of down-regulating immune responses, and they are likely to represent a population of regulatory T cells that normally plays a role in maintaining peripheral tolerance.

The development of insulin-dependent diabetes mellitus in non-obese diabetic mice: the role of CD4+ and CD8+ T cells

1991 ◽  
Vol 19 (1) ◽  
pp. 187-191 ◽  
Author(s):  
Anne-Marie Varey ◽  
Patricia Hutchings ◽  
Lorraine O'Reilly ◽  
Tracey Hussell ◽  
Herman Waldmann ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
T Cells ◽  
Cd8 T Cells ◽  
Insulin Dependent Diabetes Mellitus ◽  
Insulin Dependent Diabetes ◽  
Dependent Diabetes Mellitus ◽  
Diabetic Mice ◽  
Insulin Dependent
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