Resistance of the target islet tissue to autoimmune destruction contributes to genetic susceptibility in Type 1 diabetes (original) (raw)
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European Journal of Immunology, 2000
Autoimmune diabetes results from destruction of pancreatic g -cells by islet-infiltrating leukocytes. Different molecular mechanisms seem to be involved in this destruction but the results from many studies have not provided a clear picture so far. Therefore, we have developed a multiplex single-cell reverse transcription polymerase chain reaction to analyze the expression of genes of the tumor necrosis factor receptor (TNFR) family in pancreatic g -cells during the development of autoimmune diabetes in a TCR-HA × INS-HA double transgenic as well as a non-obese diabetic (NOD) animal model. To this end we have followed the expression of cell surface receptors of the TNFR family in NOD mice as well as in double transgenic mice that express in their T cells class II MHC-restricted TCR specific for peptide 111-119 from influenza hemagglutinin (TCR-HA) as well as hemagglutinin under the control of the rat insulin promoter (INS-HA). Both types of mice develop insulitis and diabetes spontaneously. The data show a significant increase in the expression of Fas and TNFR2 (p75) during the development of insulitis, whereas TNFR1 (p55) is already expressed in g -cells before the onset of insulitis. As ligands for these receptors are already expressed at high levels during the phase of insulitis, it is possible that g -cell death is regulated by intracellular inhibitors of apoptosis pathways.
Journal of Cellular Biochemistry, 2008
Type 1 diabetes results from the T cell-mediated destruction of pancreatic beta cells. Islet transplantation has recently become a potential therapeutic approach for patients with type 1 diabetes. However, islet-graft failure appears to be a challenging issue to overcome. Thus, complementary gene therapy strategies are needed to improve the islet-graft survival following transplantation. Immune modulation through gene therapy represents a novel way of attacking cytotoxic T cells targeting pancreatic islets. Various death ligands of the TNF family such as FasL, TNF, and TNF-Related Apoptosis-Inducing Ligand (TRAIL) have been studied for this purpose. The over-expression of TNF or FasL in pancreatic islets exacerbates the onset of type 1 diabetes generating lymphocyte infiltrates responsible for the inflammation. Conversely, the lack of TRAIL expression results in higher degree of islet inflammation in the pancreas. In addition, blocking of TRAIL function using soluble TRAIL receptors facilitates the onset of diabetes. These results suggested that contrary to what was observed with TNF or FasL, adenovirus mediated TRAIL gene delivery into pancreatic islets is expected to be therapeutically beneficial in the setting of experimental models of type 1 diabetes. In conclusion; this study mainly reveals the fundamental principles of death ligand-mediated immune evasion in diabetes mellitus.
Journal of Experimental Medicine
Lately, TNFoL 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 TNFoL in insulin-dependent diabetes mellitus (IDDM), we have generated nonobese diabetic (NOD) transgenic mice expressing TNFe¢ under the control of the rat insulin II promotor (RIP). In transgenic mice, TNFot expression on the islets resulted in massive insulitis, composed ofCD4+ T cells, CD8+ T cells, and B cells. Despite infiltration of considerable number of lymphoid cells in islets, expression of TNFc¢ protected NOD mice from IDDM. To determine the mechanism of TNFot action, splenic cells from control NOD and 1LIP-TNFc~ 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 1LIP-TNF(x transgenic mice did not induce diabetes m NOD-SCID recipients. Diabetes was induced however, in the 1LIP-TNFo~ transgenic mice when CD8+ diabetogenic cloned T cells or splenic cells from diabetic NOD mice were adoptively transferred to these mice. Furthermore, expression of TNFcx in islets also downregulated splenic cell responses to autoantigens. These data establish a mechanism of TNFcx action and provide evidence that local expression of TN&x protects NOD mice from autoimmune diabetes by preventing the development ofautoreactive islet-specific T cells. j. Exp. Med.
Significant Role for Fas in the Pathogenesis of Autoimmune Diabetes
The Journal of Immunology, 2000
Programmed cell death represents an important pathogenic mechanism in various autoimmune diseases. Type I diabetes mellitus (IDDM) is a T cell-dependent autoimmune disease resulting in selective destruction of the β cells of the islets of Langerhans. β cell apoptosis has been associated with IDDM onset in both animal models and newly diagnosed diabetic patients. Several apoptotic pathways have been implicated in β cell destruction, including Fas, perforin, and TNF-α. Evidence for Fas-mediated lysis of β cells in the pathogenesis of IDDM in nonobese diabetic (NOD) mice includes: 1) Fas-deficient NOD mice bearing the lpr mutation (NOD-lpr/lpr) fail to develop IDDM; 2) transgenic expression of Fas ligand (FasL) on β cells in NOD mice may result in accelerated IDDM; and 3) irradiated NOD-lpr/lpr mice are resistant to adoptive transfer of diabetes by cells from NOD mice. However, the interpretation of these results is complicated by the abnormal immune phenotype of NOD-lpr/lpr mice. Here...
Lately, TNFoL 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 TNFoL in insulin-dependent diabetes mellitus (IDDM), we have generated nonobese diabetic (NOD) transgenic mice expressing TNFe¢ under the control of the rat insulin II promotor (RIP). In transgenic mice, TNFot expression on the islets resulted in massive insulitis, composed ofCD4+ T cells, CD8+ T cells, and B cells. Despite infiltration of considerable number of lymphoid cells in islets, expression of TNFc¢ protected NOD mice from IDDM. To determine the mechanism of TNFot action, splenic cells from control NOD and 1LIP-TNFc~ 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 1LIP-TNF(x transgenic mice did not induce diabetes m NOD-SCID recipients. Diabetes was induced however, in the 1LIP-TNFo~ transgenic mice when CD8+ diabetogenic cloned T cells or splenic cells from diabetic NOD mice were adoptively transferred to these mice. Furthermore, expression of TNFcx in islets also downregulated splenic cell responses to autoantigens. These data establish a mechanism of TNFcx action and provide evidence that local expression of TN&x protects NOD mice from autoimmune diabetes by preventing the development ofautoreactive islet-specific T cells. 1963 j. Exp. Med.
Selective death of autoreactive T cells in human diabetes by TNF or TNF receptor 2 agonism
Proceedings of the National Academy of Sciences, 2008
Human autoimmune (AI) diseases are difficult to treat, because immunosuppressive drugs are nonspecific, produce high levels of adverse effects, and are not based on mechanistic understanding of disease. Destroying the rare autoreactive T lymphocytes causing AI diseases would improve treatment. In animal models, TNF selectively kills autoreactive T cells, thereby hampering disease onset or progression. Here, we seek to determine, in fresh human blood, whether TNF or agonists of TNF selectively kill autoreactive T cells, while sparing normal T cells. We isolated highly pure CD4 or CD8 T cells from patients with type 1 diabetes (n ؍ 675), other AI diseases, and healthy controls (n ؍ 512). Using two cell death assays, we found that a subpopulation of CD8, but not CD4, T cells in patients' blood was vulnerable to TNF or TNF agonist-induced death. One agonist for the TNFR2 receptor exhibited a doseresponse pattern of killing. In type 1 diabetes, the subpopulation of T cells susceptible to TNF or TNFR2 agonist-induced death was traced specifically to autoreactive T cells to insulin, a known autoantigen. Other activated and memory T cell populations were resistant to TNF-triggered death. This study shows that autoreactive T cells, although rare, can be selectively destroyed in isolated human blood. TNF and a TNFR2 agonist may offer highly targeted therapies, with the latter likely to be less systemically toxic. agonist antibodies ͉ autoimmunity ͉ apoptosis ͉ TNFR2 ͉ Crohn's Results Quality Blood Preparations Improve Ability to Track the Death of Diabetic T Cells with TNF Exposures. For Ͼ40 years, human blood lymphocytes for various studies have been obtained with Ficoll
Autoimmune islet destruction in spontaneous type 1 diabetes is not β-cell exclusive
Nature Medicine, 2003
, which express glial fibrillary acidic protein (GFAP) and S100β. pSC-autoreactive T-and B-cell responses arise in 3-to 4-week-old diabetes-prone non-obese diabetic (NOD) mice, followed by progressive pSC destruction before detectable β-cell death. Humans with probable prediabetes generate similar autoreactivities, and autoantibodies in islet-cell autoantibody (lCA) -positive sera co-localize to pSC. Moreover, GFAP-specific NOD T-cell lines transferred pathogenic peri-insulitis to NOD/severe combined immunodeficient (NOD/SCID) mice, and immunotherapy with GFAP or S100β prevented diabetes. pSC survived in rat insulin promoter Iymphocytic choriomeningitis virus (rip-LCMV) glycoprotein/CD8 + T-cell receptor gp double-transgenic mice with virus-induced diabetes, suggesting that pSC death is not an obligate consequence of local inflammation and βcell destruction. However, pSC were deleted in spontaneously diabetic NOD mice carrying the CD8 + /8.3 T-cell receptor transgene, a T cell receptor commonly expressed in earliest islet infiltrates. Autoimmune targeting of pancreatic nervous system tissue elements seems to be an integral, early part of natural type 1 diabetes.
Central Role of Defective Interleukin-2 Production in the Triggering of Islet Autoimmune Destruction
Immunity, 2008
The dynamics of CD4 + effector T (Teff)cells and CD4 + Foxp3 + regulatory T (Treg)cells during diabetes progression in non-obese diabetic mice was investigated to determine if an imbalance of Treg cells and Teff cells contributes to the development of type 1 diabetes. Our results demonstrated a progressive decrease in the Treg:Teff ratio in inflamed islets, but not in pancreatic lymph nodes. Intra-islet Treg cells expressed reduced amounts of CD25 and Bcl-2 suggesting that their decline was due to increased apoptosis. Additionally, administration of low dose interleukin-2 (IL-2) promoted Treg cell survival and protected mice from developing diabetes. Together, these results suggest intra-islet Treg cell dysfunction secondary to defective IL-2 production is a root cause of the progressive breakdown of self-tolerance and development of diabetes in the non-obese diabetic mice.