Oral probiotic administration induces interleukin-10 production and prevents spontaneous autoimmune diabetes in the non-obese diabetic mouse (original) (raw)
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IL-33 Prevents MLD-STZ Induction of Diabetes and Attenuate Insulitis in Prediabetic NOD Mice
Frontiers in Immunology
Type 1 diabetes is an autoimmune disease caused by the immune-mediated destruction of pancreatic β-cells. Prevention of type 1 diabetes requires early intervention in the autoimmune process against beta-cells of the pancreatic islets of Langerhans, which is believed to result from disordered immunoregulation. CD4 + Foxp3 + regulatory T cells (Tregs) participate as one of the most important cell types in limiting the autoimmune process. The aim of this study was to investigate the effect of exogenous IL-33 in multiple low dose streptozotocin (MLD-STZ) induced diabetes and to delineate its role in the induction of protective Tregs in an autoimmune attack. C57BL/6 mice were treated i. p. with five doses of 40 mg/kg STZ and 0.4 µg rIL-33 four times, starting from day 0, 6, or 12 every second day from the day of disease induction. 16 weeks old NOD mice were treated with 6 injections of 0.4 µg/mouse IL-33 (every second day). Glycemia and glycosuria were measured and histological parameters in pancreatic islets were evaluated at the end of experiments. Cellular make up of the pancreatic lymph nodes and islets were evaluated by flow cytometry. IL-33 given simultaneously with the application of STZ completely prevented the development of hyperglycemia, glycosuria and profoundly attenuated mononuclear cell infiltration. IL-33 treatment was accompanied by higher number of IL-13 and IL-5 producing CD4 + T cells and increased presence of ST2 + Foxp3 + regulatory T cells in pancreatic lymph nodes and islets. Elimination of Tregs abrogated protective effect of IL-33. We provide evidence that exogenous IL-33 completely prevents the development of T cell mediated inflammation in pancreatic islets and consecutive development of diabetes in C57BL/6 mice by facilitating the induction Treg cells. To extend this finding for possible relevance in spontaneous diabetes, we showed that IL-33 attenuate insulitis in prediabetic NOD mice.
Endocrinology, 1997
To evaluate the effect of antigen-pulsed dendritic cell (DC) transfer on the development of diabetes, 5-week-old female NOD mice received a single iv injection of splenic syngeneic DC from euglycemic NOD mice pulsed in vitro with human ␥ globulin (HGG). Eleven of 12 mice were protected from the development of diabetes up to the age of 25 weeks, and the insulitis score was significantly reduced. In contrast, NOD mice receiving unpulsed splenic DCs showed histological signs of insulitis and course of type 1 diabetes similar to untreated NOD mice. Treatment with HGG-pulsed DC was associated with profound modifications of cytokine secretory capacities within the islets. Thus, supernatants of islets from these mice contained increased levels of interleukin (IL)-4, IL-10, and, to a lesser extent, interferon-␥ and diminished levels of tumor necrosis factor-␣ compared with controls. Because exogenous IL-4 and IL-10 exert antidiabetogenic effect in NOD mice and early blockade of endogenous tumor necrosis factor-␣ prevents NOD mouse diabetes, these phenomena may be causally related to the antidiabetogenic effect of HGG-pulsed DC treatment. (Endocrinology
Role of immune system modulation in prevention of type 1 diabetes mellitus
Indian Journal of Endocrinology and Metabolism, 2012
An increased incidence of Type 1 diabetes mellitus (T1DM) is expected worldwide. Eventually, T1DM is fatal unless treated with insulin. The expansion of interventions to prevent diabetes and the use of alternative treatments to insulin is a dream to be fulfi lled. The pathophysiology in T1DM is basically a destruction of beta cells in the pancreas, regardless of which risk factors or causative entities have been present. Individual risk factors can have separate patho-physiological processes to, in turn, cause this beta cell destruction. Currently, autoimmunity is considered the major factor in the pathophysiology of T1DM. In a genetically susceptible individual, viral infection may stimulate the production of antibodies against a viral protein that trigger an autoimmune response against antigenically similar beta cell molecules. Many components of the immune system have been implicated in autoimmunity leading to -cell destruction, including cytotoxic and helper T-cells, B-cells, macrophages, and dendritic cells. The infl ammatory process in early diabetes is thought to be initiated and propagated by the effect of Th1-secreted cytokines (e.g. g interferon) and suppressed by Th2-secreted antiinfl ammatory cytokines (interleukins). Structure and function of -cell may be modulated by using Th1/Th2-secreted cytokines. Several experimental and clinical trials of applying GAD65, Hsp60, peptide-MHC, pepetide-277 immunization, anti-CD3 infusion, and interleukins to modulate immune response in T1DM were done. Applying such trials in patients with prediabetes, will most likely be the future key in preventing Type 1 autoimmune diabetes.
Diabetes, 2009
OBJECTIVE-The autoimmune destruction of -cells in type 1 diabetes results in a loss of insulin production and glucose homeostasis. As such, an immense interest exists for the development of therapies capable of attenuating this destructive process through restoration of proper immune recognition. Therefore, we investigated the ability of the immune-depleting agent antithymocyte globulin (ATG), as well as the mobilization agent granulocyte colony-stimulating factor (GCSF), to reverse overt hyperglycemia in the nonobese diabetic (NOD) mouse model of type 1 diabetes.
Total lymphoid irradiation prevents diabetes mellitus in the Bio-Breeding/Worcester (BB/W) rat
Diabetes, 1984
Total lymphoid irradiation (TLI) at doses of 2200 rads or greater prevented diabetes in susceptible BB/W rats. Two of 29 (7%) treated rats became diabetic compared with 23 of 39 (59%) controls (P < 0.001). TLI did not, however, prevent insulitis or thyroiditis in nondiabetic rats, nor did it restore the depressed concanavalin-A responsiveness of BB rat lymphocytes. T-lymphocyte subset proportions were the same in both groups. TLI was associated with significant radiationrelated mortality, and nondiabetic TLI-treated rats weighed significantly less than controls. We conclude that TLI is effective in the prevention of BB rat diabetes. However, TLI fails to correct the subclinical immunologic abnormalities of the model and is associated with significant morbidity. DIABETES 33:543-547, June 1984. T he Bio-Breeding (BB) rat 1 develops a syndrome of spontaneous diabetes that shares many of the characteristics of human insulin-dependent diabetes mellitus (IDDM). The rats are lean and develop acute hyperglycemia with ketonemia between 60 and 120 days of age. Equal numbers of males and females develop the syndrome, and most affected animals die within 2 wk unless treated with insulin. The presence of lymphocytic insulitis suggests a cell-mediated autoimmune pathogenesis of the syndrome. Additional data that support this hypothesis include the finding of-circulating autoantibodies, 24 the passive transfer of BB diabetes 5 and insulitis, 6 and prevention of the disorder by immunosuppression. 7-9
Diabetes, 2005
The onset of type 1 diabetes in NOD mice is delayed by oral administration of a bacterial extract (OM-85) and can be completely prevented by its intraperitoneal administration. Optimal prevention is observed when starting treatment at 3 or 6 weeks of age, and some effect is still observed with treatment at 10 weeks of age. Using genetically deficient mice and cytokine-neutralizing monoclonal antibodies, we demonstrate here that the therapeutic effect does not involve T-helper type 2 cytokines (interleukin [IL]-4 and -10) but is tightly dependent on transforming growth factor (TGF)-β. Natural killer T-cells also participate in the therapeutic effect because CD1d−/− NOD mice are partially resistant to the protective effect of OM-85. The question remains of the specificity of the protective effect of OM-85, which may include proinflammatory components. It will thus be important to further characterize the molecular components that afford protection from type 1 diabetes. Lipopolysacchar...
Interleukin-13 prevents autoimmune diabetes in NOD mice
Diabetes, 1999
Interleukin (IL)-13 is a cytokine primarily produced by the T-helper (Th)-2 subset of lymphocytes that possesses powerful anti-inflammatory properties. Here, we have evaluated the impact of IL-13 treatment on development of type 1 diabetes in diabetes-prone nonobese diabetic (NOD) mice. Prolonged treatment with recombinant human IL-13 (hIL-13) markedly diminished the incidence of spontaneous type 1 diabetes in the mice. Female NOD mice treated from age 5-16 weeks with h I L -13 also showed significantly milder insulitis than control mice. The preventive action of hIL-13 was associated with a slight but significant change from a type 1 to a type 2 cytokine response. Accordingly, splenic lymphoid
Diabetologia, 2011
Aims/hypothesis Microbial factors influence the development of diabetes in NOD mice. Studies in germ-free animals have revealed important roles of microbiota in the regulation of Th17 and forkhead box P3 (FOXP3) + T regulatory (Treg) activation in the intestine. However, the effects of intestinal microbiota in immune regulation and diabetes development in NOD mice are still poorly understood. Methods A colony of germ-free NOD mice was established to evaluate the effects of intestinal microbiota on regulatory immunity in the gut, and on the development of insulitis and diabetes in NOD mice. Results Diabetes developed in roughly equal numbers in germ-free and specific pathogen-free NOD mice. Insulitis was accentuated in germ-free NOD mice; yet insulin preservation was unaltered. Germ-free NOD mice showed increased levels of Il17 (also known as Il17a) mRNA in the colon, and of Th17 and Th1 cells in the mesenteric and pancreatic lymph nodes, while Foxp3 mRNA and FOXP3 + Tregs were reduced. In the islet infiltrates, FOXP3 + CD4 + T cells were slightly increased in germ-free mice. B cells appeared less activated in the peritoneum and were less abundant in islet infiltrates. Conclusions/interpretation These results indicate that lack of intestinal microbiota promotes an imbalance between Th1, Th17 and Treg differentiation in the intestine. This imbalance is associated with accelerated insulitis, but intact recruitment of FOXP3 + Tregs into islets, suggesting: (1) a microbial dependence of local induction of Treg in the gut and draining lymph nodes; but (2) a potentially compensatory function of naturally occurring Tregs in the islets, which may help control diabetogenic T cells.