T‐lymphocytes and the pathogenesis of type 1 (insulin‐dependent) diabetes mellitus

Roep, Bart O.; Vries, R. R. P. De

doi:10.1111/j.1365-2362.1992.tb01433.x

Cited by 28 publications

(14 citation statements)

References 174 publications

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“…Several observations in humans and experimental models in rodents indicate that activated T cells are critical for the destruction of ␤ cells in T1D: 1) T cells infiltrate the pancreatic islets at disease onset (45,(52)(53)(54); 2) T cell-directed immunosuppressants delay the onset of T1D (55, 56); 3) T1D can be transferred from a diabetic patient to an immunosuppressed nondiabetic recipient by BM transplantation (57); 4) T1D can be adoptively transferred to nondiabetic NOD or NODscid mice using splenocytes, T lymphocytes (31,58,59) or T cell clones isolated from diabetic NOD mice (41, 60); 5) neonatal thymectomy prevents diabetes in NOD mice (61); 6) NODnu/nu mice do not develop diabetes (62); and 7) ␤ cell-specific T cells have been detected in prediabetic or recentonset T1D patients (63,64). Therefore, effective treatment of T1D will require the elimination of those diabetogenic T lymphocytes that initiate and perpetuate the destruction of the pancreatic ␤ cells.…”

Section: Discussionmentioning

confidence: 99%

Dendritic Cells Expressing Transgenic Galectin-1 Delay Onset of Autoimmune Diabetes in Mice

Perone

Bertera

Tawadrous

et al. 2006

The Journal of Immunology

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Type 1 diabetes (T1D) is a disease caused by the destruction of the β cells of the pancreas by activated T cells. Dendritic cells (DC) are the APC that initiate the T cell response that triggers T1D. However, DC also participate in T cell tolerance, and genetic engineering of DC to modulate T cell immunity is an area of active research. Galectin-1 (gal-1) is an endogenous lectin with regulatory effects on activated T cells including induction of apoptosis and down-regulation of the Th1 response, characteristics that make gal-1 an ideal transgene to transduce DC to treat T1D. We engineered bone marrow-derived DC to synthesize transgenic gal-1 (gal-1-DC) and tested their potential to prevent T1D through their regulatory effects on activated T cells. NOD-derived gal-1-DC triggered rapid apoptosis of diabetogenic BDC2.5 TCR-transgenic CD4+ T cells by TCR-dependent and -independent mechanisms. Intravenously administered gal-1-DC trafficked to pancreatic lymph nodes and spleen and delayed onset of diabetes and insulitis in the NODrag1−/− lymphocyte adoptive transfer model. The therapeutic effect of gal-1-DC was accompanied by increased percentage of apoptotic T cells and reduced number of IFN-γ-secreting CD4+ T cells in pancreatic lymph nodes. Treatment with gal-1-DC inhibited proliferation and secretion of IFN-γ of T cells in response to β cell Ag. Unlike other DC-based approaches to modulate T cell immunity, the use of the regulatory properties of gal-1-DC on activated T cells might help to delete β cell-reactive T cells at early stages of the disease when the diabetogenic T cells are already activated.

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Section: Discussionmentioning

confidence: 99%

Dendritic Cells Expressing Transgenic Galectin-1 Delay Onset of Autoimmune Diabetes in Mice

Perone

Bertera

Tawadrous

et al. 2006

The Journal of Immunology

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“…In this model, diabetes onset is more rapid (days [20][21][22][23][24][25][26][27][28][29][30] and aggressive than the natural progression of the disease in NOD mice. Curcumin treatment significantly delayed the onset of T1DM (median = 49 days) in comparison to the control group (median = 29 days; P < 0·001 versus control, by log-rank test) (Fig.…”

Section: Administration Of Curcumin Delays Disease Onset Employing Thmentioning

confidence: 99%

“…Islet infiltration (insulitis) initiates the destruction of β cells and, eventually, diabetes [29]. To investigate whether curcumin administration in NODscid mice reconstituted with diabetogenic splenocytes had an effect on islet infiltration, we harvested pancreata for histological analysis after 20 or 35 days after adoptive disease transfer.…”

Section: Curcumin Inhibits Pancreatic Leucocyte Infiltrationmentioning

confidence: 99%

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Curcumin ameliorates autoimmune diabetes. Evidence in accelerated murine models of type 1 diabetes

Castro

Tabarrozzi

Winnewisser

et al. 2014

Clinical and Experimental Immunology

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SummaryType 1 diabetes (T1DM) is a T cell-mediated autoimmune disease that selectively destroys pancreatic β cells. The only possible cure for T1DM is to control autoimmunity against β cell-specific antigens. We explored whether the natural compound curcumin, with anti-oxidant and anti-inflammatory activities, might down-regulate the T cell response that destroys pancreatic β cells to improve disease outcome in autoimmune diabetes. We employed two accelerated autoimmune diabetes models: (i) cyclophosphamide (CYP) administration to non-obese diabetic (NOD) mice and (ii) adoptive transfer of diabetogenic splenocytes into NODscid mice. Curcumin treatment led to significant delay of disease onset, and in some instances prevented autoimmune diabetes by inhibiting pancreatic leucocyte infiltration and preserving insulin-expressing cells. To investigate the mechanisms of protection we studied the effect of curcumin on key immune cell populations involved in the pathogenesis of the disease. Curcumin modulates the T lymphocyte response impairing proliferation and interferon (IFN)-γ production through modulation of T-box expressed in T cells (T-bet), a key transcription factorfor proinflammatory T helper type 1 (Th1) lymphocyte differentiation, both at the transcriptional and translational levels. Also, curcumin reduces nuclear factor (NF)-κB activation in T cell receptor (TCR)-stimulated NOD lymphocytes. In addition, curcumin impairs the T cell stimulatory function of dendritic cells with reduced secretion of proinflammatory cytokines and nitric oxide (NO) and low surface expression of co-stimulatory molecules, leading to an overall diminished antigen-presenting cell activity. These in-vitro effects correlated with ex-vivo analysis of cells obtained from curcumin-treated mice during the course of autoimmune diabetes. These findings reveal an effective therapeutic effect of curcumin in autoimmune diabetes by its actions on key immune cells responsible for β cell death.

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“…Type 1 diabetes develops as a result of beta-cell destruction mediated by an autoimmune process where T cells play the major role (Roep & De Vries 1992, Yoon et al 1998. Environmental factors have been proposed as possible triggers of beta-cell autoimmunity in genetically predisposed individuals (Akerblom & Knip 1998).…”

Section: Introductionmentioning

confidence: 99%

Establishment of T cell lines to bovine beta-casein and beta-casein-derived epitopes in patients with type 1 diabetes

Monetini

Barone²,

Stefanini³

et al. 2003

Journal of Endocrinology

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Enhanced cellular immune response to bovine -casein has been reported in patients with type 1 diabetes. In this study we aimed to establish -casein-specific T cell lines from newly diagnosed type 1 diabetic patients and to characterise these cell lines in terms of phenotype and epitope specificity. Furthermore, since sequence homologies exist between -casein and putative beta-cell autoantigens, reactivity to the latter was also investigated.T cell lines were generated from the peripheral blood of nine recent onset type 1 diabetic patients with different HLA-DQ and -DR genotypes, after stimulation with antigen pulsed autologous irradiated antigen presenting cells (APCs) and recombinant human interleukin-2 (rhIL-2). T cell line reactivity was evaluated in response to bovine -casein, to 18 overlapping peptides encompassing the whole sequence of -casein and to beta-cell antigens, including the human insulinoma cell line, CM, and a peptide from the beta-cell glucose transporter, GLUT-2. T cell lines specific to -casein could not be isolated from HLA-matched and -unmatched control subjects.-Casein T cell lines reacted to different sequences of the protein, however a higher frequency of T cell reactivity was observed towards the C-terminal portion (peptides B05-14, and B05-17 in 5/9 and 4/9 T cell lines respectively). Furthermore, we found that 1 out of 9 -casein-specific T cell lines reacted also to the homologous peptide from GLUT-2, and that 3 out of 4 of tested cell lines reacted also to extracts of the human insulinoma cell line, CM.We conclude that T cell lines specific to bovine -casein can be isolated from the peripheral blood of patients with type 1 diabetes; these cell lines react with multiple and different sequences of the protein particularly towards the C-terminal portion. In addition, reactivity of -casein T cell lines to human insulinoma extracts and GLUT-2 peptide was detected, suggesting that the potential cross-reactivity with beta-cell antigens deserves further investigation.

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T‐lymphocytes and the pathogenesis of type 1 (insulin‐dependent) diabetes mellitus

Cited by 28 publications

References 174 publications

Dendritic Cells Expressing Transgenic Galectin-1 Delay Onset of Autoimmune Diabetes in Mice

Dendritic Cells Expressing Transgenic Galectin-1 Delay Onset of Autoimmune Diabetes in Mice

Curcumin ameliorates autoimmune diabetes. Evidence in accelerated murine models of type 1 diabetes

Establishment of T cell lines to bovine beta-casein and beta-casein-derived epitopes in patients with type 1 diabetes

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