Role of T-cell anergy and suppression in susceptibility to IDDM

Bergerot, Isabelle; Arreaza, Guillermo; Cameron, Mark J.; Chou, Henry; Delovitch, Terry L.

doi:10.1016/s0923-2494(97)87245-8

Cited by 16 publications

(17 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We and others have previously suggested that tolerance induction in the NOD mouse may be impeded by the hypoproliferative phenotype illustrated in the CD4 T-cell compartment (4,14,39,40). However, the data here suggest that the proliferative phenotype of the peripheral T-cell compartment is not predictive of disease development.…”

Section: Discussioncontrasting

confidence: 82%

NOD B-cells Are Insufficient to Incite T-Cell-Mediated Anti-islet Autoimmunity

et al. 2005

View full text Add to dashboard Cite

Although it is well established that B-cells are required for the development of diabetes in the nonobese diabetic (NOD) mouse, the nature of their role remains unknown. Herein, we investigate the hypothesis that B-cells in this autoimmune background actively disrupt the tolerant state of those T-cells with which they interact. We demonstrate that NOD B-cells express elevated levels of crucial molecules involved in antigen presentation (including CD21/35, major histocompatibility complex class II, and CD40), alterations that invite the possibility of inappropriate T-cell activation. However, when chimeric animals are generated in which all B-cells are NOD-derived, a tolerant state is maintained. These data demonstrate that although B-cells are required for the development of autoimmunity, they are not sufficient to disrupt established tolerance. However, the mechanism by which B-cells promote the development of diabetes remains unknown. Data from our laboratory suggests that the requisite function of B-cells results from the inability of non-␤-cell APC subsets to promote proliferation of T-cells in the nonobese diabetic (NOD) mouse (13,14). Therefore, the NOD B-cell pool is the only efficient coactivator of T-cell reactivity. Yet, it remains unknown whether peripheral tolerance is disrupted by interaction with these B-cells or rather is never established secondary to inactivity on the part of other thymic or peripheral APCs. Here, we address this question with a chimeric system in which all B-cells are NOD derived.Progeny resulting from intercrosses between the NOD mouse and other nonautoimmune strains are uniformly protected from the development of diabetes (15-17). However, lethal irradiation of these mice and reconstitution with NOD bone marrow restores the progression to islet destruction and disease. The addition of F1-derived bone marrow to this inoculum has been reported to restore the protection from diabetes. These data suggest that cells derived from the F1 bone marrow prevent the realization of the pathogenic potential inherent in NOD bone marrow derivatives (18,19). The adaptation of this system presented here permits the evaluation of T-cell activation and tolerance in the presence of NOD-derived B-cells. These data suggest that tolerance can be maintained in the presence of this repertoire, that autoimmunity likely results from the absence of critical tolerance promoting factors within another APC subset, and that NOD-derived B-cells are insufficient to drive T-cell-mediated autoimmunity. RESEARCH DESIGN AND METHODSNOD/LtJ, NOD.NONThy1.1, C57BL/6, and C57BL/6 MT Ϫ/Ϫ mice were purchased from The Jackson Laboratories (Bar Harbor, ME). All other strains (F1.g7, F1MTϪ/Ϫ , NOD MT Ϫ/Ϫ , and B6.g7) were derived from stocks maintained in our facility. All mice were housed under specific pathogen-free barrier conditions and maintained according to the guidelines for use and care of laboratory animals as set forth by the University of Pennsylvania. All NOD mice and chimera were monitored weekly for the devel...

show abstract

Section: Discussioncontrasting

confidence: 82%

NOD B-cells Are Insufficient to Incite T-Cell-Mediated Anti-islet Autoimmunity

et al. 2005

View full text Add to dashboard Cite

show abstract

“…Considerable evidence suggests a role for these autoantigens in the pathogenesis of T1D in humans (9, 14, 17, 28 -31), NOD mice (2,3,15,21,(32)(33)(34)(35)(36), and Bio-Breeding rats (12). In NOD mice, T cell autoreactivity to hGAD65 (37,38) and mGAD67 (21) was reported to precede that to insulin (3), indicating that insulin may not be an early target autoantigen in T1D.…”

Section: Discussionmentioning

confidence: 99%

“…Data are expressed as mean SI Ϯ SD. peripheral regulatory mechanisms may control this autoreactivity in diabetes-resistant mice (27,32). The failure of immunoregulation leading to T1D in NOD mice (1,24) is likely to be reflected by the expansion of islet ␤ cell Ag-reactive T cells present in peripheral lymphoid tissues, such as the spleen.…”

Section: Discussionmentioning

confidence: 99%

Evidence That a Peptide Spanning the B-C Junction of Proinsulin Is an Early Autoantigen Epitope in the Pathogenesis of Type 1 Diabetes

Chen

Bergerot

Elliott

et al. 2001

The Journal of Immunology

103

View full text Add to dashboard Cite

The expression of pro(insulin) in the thymus may lead to the negative selection of pro(insulin) autoreactive T cells and peripheral tolerance to this autoantigen in type 1 diabetes (T1D). We investigated whether proinsulin is expressed in the thymus of young nonobese diabetic (NOD) mice, whether T cells from naive NOD female mice at weaning are reactive to mouse proinsulin, and the role of proinsulin as a pathogenic autoantigen in T1D. Proinsulin II mRNA transcripts were detected in the thymus of 2-wk-old NOD mice at similar levels to other control strains. Despite this expression, proinsulin autoreactive T cells were detected in the periphery of 2- to 3-wk-old naive NOD mice. Peripheral T cells reactive to the insulin, glutamic acid decarboxylase 65 (GAD65), GAD67, and islet cell Ag p69 autoantigens were also detected in these mice, indicating that NOD mice are not tolerant to any of these islet autoantigens at this young age. T cell reactivities to proinsulin and islet cell Ag p69 exceeded those to GAD67, and T cell reactivity to proinsulin in the spleen and pancreatic lymph nodes was directed mainly against a p24–33 epitope that spans the B chain/C peptide junction. Intraperitoneal immunization with proinsulin perinatally beginning at 18 days of age delayed the onset and reduced the incidence of T1D. However, s.c. immunization with proinsulin initiated at 5 wk of age accelerated diabetes in female NOD mice. Our findings support the notion that proinsulin p24–33 may be a primary autoantigen epitope in the pathogenesis of T1D in NOD mice.

show abstract

“…During the development of autoimmune diabetes, there is an important change in T-cell immunoregulation that occurs by the age of 4-6 wk in NOD mice, the skewing toward to Th1 cells. This phenomenon was reflected by the cytokine secretion profiles of islet-infiltrating T cells that have a high ratio of IFN-g/IL-4 expression [24,25]. Intervention of this cytokine imbalance by autoantigen-specific tolerance induction, by costimulation blockade or by overexpression of IL-4 could prevent diabetic progression.…”

mentioning

confidence: 99%

Attenuation of Th1 response through galectin‐9 and T‐cell Ig mucin 3 interaction inhibits autoimmune diabetes in NOD mice

2009

View full text Add to dashboard Cite

Galectin-9 (gal-9), widely expressed in many tissues, regulates Th1 cells and induces their apoptosis through its receptor, T-cell Ig mucin 3, which is mainly expressed on terminally differentiated Th1 cells. Type 1 diabetes is a Th1-dominant autoimmune disease that specifically destroys insulin-producing b cells. To suppress the Th1 immune response in the development of autoimmune diabetes, we overexpressed gal-9 in NOD mice by injection of a plasmid encoding gal-9. Mice treated with gal-9 plasmid were significantly protected from diabetes and showed less severe insulitis compared with controls. Flow cytometric analyses in NOD-T1/2 double transgenic mice showed that Th1-cell population in spleen, pancreatic lymph node and pancreas was markedly decreased in gal-9 plasmidtreated mice, indicating a negative regulatory role of gal-9 in the development of pathogenic Th1 cells. Splenocytes from gal-9 plasmid-treated mice were less responsive to mitogenic stimulation than splenocytes from the control group. However, adoptive transfer of splenocytes from gal-9-treated or control mice caused diabetes in NOD/SCID recipients with similar kinetics, suggesting that gal-9 treatment does not induce active tolerance in NOD mice. We conclude that gal-9 may downregulate Th1 immune response in NOD mice and could be used as a therapeutic target in autoimmune diabetes.Key words: Galectin-9 . Th1 . T-cell Ig mucin 3 . Type 1 diabetes IntroductionWhen CD4 1 Th cells interact with class II MHC-peptide complex and costimulatory molecules on APC, they differentiate into several effector subsets. There are two major Th subsets that have unique patterns of cytokine secretion and different functional properties. Th1 cells produce cytokines such as IFN-g, IL-2, TNF-a and lymphotoxin that are commonly associated with cellmediated immune responses against intracellular pathogens, delayed-type hypersensitivity and induction of organ-specific autoimmune diseases. Th2 cells produce cytokines such as IL-4, IL-5, IL-10 and IL-13 that are crucial for controlling extracellular helminth infections and promoting atopic and allergic diseases [1,2].Type 1 diabetes (T1D) is a T-cell-mediated autoimmune disease that selectively destroys the insulin-producing b cells in the pancreas. NOD mice spontaneously develop autoimmune diabetes with immunopathological features resembling those of human disease and can be used as an animal model to study the pathogenesis of T1D. Previous studies have demonstrated that transfer of NOD CD4 1 T cells to immunodeficient NOD/SCID mice can induce diabetes in those recipients, indicating that CD4 1 T cells play an important role in the pathogenesis of diabetes [3,4] [12]. Previous approaches using TIM-3-Ig fusion protein to interrupt the interactions between TIM-3 and its ligand in vivo resulted in hyperproliferation of Th1 cells and release of Th1-related cytokines [13]. TIM-3 ligand was subsequently identified as galectin-9 (gal-9) [14], a b-galactoside binding lectin that belongs to a growing family of animal lectins, the...

show abstract

Role of T-cell anergy and suppression in susceptibility to IDDM

Cited by 16 publications

References 73 publications

NOD B-cells Are Insufficient to Incite T-Cell-Mediated Anti-islet Autoimmunity

NOD B-cells Are Insufficient to Incite T-Cell-Mediated Anti-islet Autoimmunity

Evidence That a Peptide Spanning the B-C Junction of Proinsulin Is an Early Autoantigen Epitope in the Pathogenesis of Type 1 Diabetes

Attenuation of Th1 response through galectin‐9 and T‐cell Ig mucin 3 interaction inhibits autoimmune diabetes in NOD mice

Contact Info

Product

Resources

About