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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin-dependent diabetes mellitus in nonobese diabetic (NOD) mice results from selective destruction of pancreatic islet beta-cells following islet infiltration by mononuclear leukocytes. Cytokines produced by islet-infiltrating mononuclear cells may be involved in beta-cell destruction. Therefore, we analyzed cytokine mRNA expression, by reverse-transcriptase PCR (RT-PCR) assay, in mononuclear leukocytes isolated from pancreatic islets of four groups of mice: diabetes-prone female NOD mice; female NOD mice protected from diabetes by injection of CFA at an early age; male NOD mice with a low diabetes incidence; and female BALB/c mice that do not develop diabetes. We found that mRNA levels of IL-1 beta, IL-2, IL-4, IL-10, and IFN-gamma in mononuclear cells from islets of diabetes-prone female NOD mice increased progressively as these cells infiltrated the islets from age 5 wk to diabetes onset (> 13 wk). However, only IFN-gamma mRNA levels were significantly higher in islet mononuclear cells from 12-wk-old diabetes-prone female NOD mice than from less diabetes-prone NOD mice (CFA-treated females, and males) and normal mice (BALB/c). In contrast, IL-4 mRNA levels were lower in islet mononuclear cells from diabetes-prone female NOD mice than from NOD mice with low diabetes incidence (CFA-treated females and males). Splenic cell mRNA levels of IFN-gamma and IL-4 were not different in the four groups of mice. These results suggest that islet beta-cell destruction and diabetes in female NOD mice are dependent upon intra-islet IFN-gamma production by mononuclear cells, and that CFA-treated female NOD mice and male NOD mice may be protected from diabetes development by down-regulation of IFN-gamma production in the islets.
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PMID:IFN-gamma gene expression in pancreatic islet-infiltrating mononuclear cells correlates with autoimmune diabetes in nonobese diabetic mice. 772 37

Freund's complete adjuvant (CFA) and BCG vaccine modulate the development of type 1 diabetes in animal models. In non-obese diabetic mice, CFA and BCG significantly reduced the proportion developing diabetes compared with controls. Histological examination showed that autoimmune disease still developed but had been diverted to become nondestructive. In a preliminary trial in 17 newly diagnosed, type 1 diabetic patients, intracutaneous administration of 0.1 mL of BCG 1 mg/mL led to clinical remission in 11 (65%)--by week 4 in 6. Remission has been sustained in 3 for 6-10 months. No side-effects were reported. A double-blind trial of BCG is warranted.
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PMID:Effect of adjuvant therapy on development of diabetes in mouse and man. 790 74

Islet transplantation can provide a therapeutic option for patients who suffer from type 1 diabetes mellitus, especially if current aggressive immunosuppression could be eliminated. In vitro immunomodulation has achieved this goal for islet allografts--however, strategies must be developed to prevent B cell lysis secondary to the chronic autoimmune process of diabetes. Previously, we have found that adjuvant therapy with CFA was effective in preventing the onset of diabetes and the recurrence of B cell lysis post-islet transplantation. In this study we evaluated the efficacy of BCG, a more clinically relevant immunoadjuvant, to prevent recurrent autoimmune damage to islets grafted into diabetic NOD mice. Highly purified islets were isolated from either 5-7-week-old prediabetic NOD mice or 5-8-week-old CBA/J mice using standard islet isolation techniques. Four hundred purified islets were transplanted into the kidney capsule of diabetic NOD recipients. A single dose of BCG was administered in recipients of syngeneic (gp 1) and allogeneic islets (gp 2). In gp 1, 8 of 10 BCG-treated syngeneic recipients remained normoglycemic for > 100 days posttransplant. In untreated recipients of syngeneic islets (gp 3) the graft failed at 19 days (n = 16) (P value, gp 1 vs. gp 3 < 0.001). In untreated allograft recipients, islet grafts functioned for 11 days (n = 8), which did not differ significantly (P = NS) from the BCG-treated allografts (gp 4) (14 days, n = 7). In 6 mice with long-term graft function, a second syngeneic graft implanted into the contralateral kidney maintained normoglycemia for 50 days following the removal of the first islet graft. Histological examination of the grafts from gp 1 mice showed granulated B cells with periinsular lymphocytes, while those of the control animals showed lytic B cells and marked lymphocytic infiltration. We conclude that adjuvant therapy with a single dose of BCG can prevent the recurrent autoimmune insulitis, but not allograft rejection in islets transplanted into NOD mice, and that a state of unresponsiveness is induced to allow acceptance of a second syngeneic graft. These data suggest that adjuvant therapy may be useful to sustain the function of transplanted islets in the type 1 diabetic.
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PMID:BCG immunotherapy prevents recurrence of diabetes in islet grafts transplanted into spontaneously diabetic NOD mice. 817 49

Insulin-dependent diabetes mellitus is an autoimmune disease that is characterized by the destruction of insulin-producing beta cells in the islet of Langerhans. We have recently reported that the induction of the disease in nonobese diabetic (NOD) mice can be prevented by a single injection of CFA. In this study, we have explored the cellular basis and the time course of the disease protection. Since CFA contains a mycobacterial cell wall that has adjuvant property, we investigated the protective role of mycobacteria in young NOD mice. Mice injected with Mycobacterium tuberculosis or Mycobacterium bovis (BCG vaccine) at 4 wk of age were also found to be protected from diabetes. We have found that complete protection from diabetes is only achieved by administration of CFA between 4 and 10 wk of age. Draining lymph node cells or spleen cells from CFA-treated NOD mice transfer the protection. Adoptive transfer of spleen cells from CFA-treated mice with spleen cells from acutely diabetic mice delayed the induction of disease into irradiated recipient mice. CFA-treated old NOD mice were also resistant to passive transfer of disease by spleen cells from acutely diabetic mice. Depletion of the Thy 1.2+ cells or CD4(+)-bearing T cells abrogated the protection. However, disease can be induced in the protected mice by cyclophosphamide treatment. We also found that thymocytes from NOD mice responded only weakly to mitogen Con A. CFA treatment, however, restored the ability of these cells to respond to Con A. Finally, our results suggest that T cells induced after CFA treatment of NOD mice prevent both the induction and effector phases of the disease.
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PMID:Complete Freund's adjuvant-induced T cells prevent the development and adoptive transfer of diabetes in nonobese diabetic mice. 843 36

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease that is characterized by the destruction of insulin-producing beta-cells in the pancreatic islets. A single administration of CFA prevents clinical hyperglycaemia in non-obese diabetic (NOD) mice. We have previously shown that CFA administration does not eliminate insulitis in the pancreas of the treated animals, but diverts the disease process from a destructive to a non-destructive pathway. We provide evidence that this phenomenon may be under cytokine control. Neutralizing monoclonal antibodies against IL-4 and IL-10 were injected, singularly or in combination, into CFA-treated NOD mice. Antibody treatment did not lead to the development of overt diabetes; however, a marked impairment of glucose tolerance was shown in about one half of the mice treated with a combination of the two antibodies at the end of the study. This functional abnormality correlated with the histological loss of pancreatic islet tissue. These studies suggest a role for IL-4 and IL-10 in CFA-induced protection from diabetes in the NOD mouse. They also suggest that, in this animal model, the nature of the autoimmune response to islet tissue (either destructive or non-destructive) may reflect the relative proportion of Th1- and Th2-type cytokines produced in the lesions.
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PMID:Protection from autoimmune diabetes by adjuvant therapy in the non-obese diabetic mouse: the role of interleukin-4 and interleukin-10. 942 94

Immunization with agonist peptides recognized by autoaggressive lymphocytes has been used successfully in several animal models for type 1 diabetes (T1D) or multiple sclerosis (MS) to prevent disease. Depending on the timing of immunization, use of adjuvant and route of administration either elimination of autoaggressive T cells or induction of regulation reflected by cytokine shifts were described. Since it was also reported that such agonist peptides could enhance autoimmunity by activating aggressive lymphocytes, our goal was to re-evaluate their efficacy in an antigen-specific model of virally-induced T1D that allowed us to precisely track the autoaggressive response. We find that rather than the route of administration (oral versus sc) the precise timing is important for inducing tolerance to self-antigens. Tolerance is transient and only immunization during a susceptible phase 10 to 20 days prior to the induction of disease but not in prediabetic mice resulted in protection. Further, use of a stronger adjuvant (CFA) compared to IFA enhanced the protective effect. Mechanistically, a transient loss of autoaggressive T cells was responsible for preventing disease, the effect was quantitative and no regulatory lymphocytes or cytokine shifts were induced by any of our treatments. Thus, MHC class I-restricted agonist peptides might only find a limited use in treating autoimmune disorders, because tolerance induction is transient and treatment has to be given very early, ideally prior to activation of the aggressive response.
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PMID:Tolerance induction with agonist peptides recognized by autoaggressive lymphocytes is transient: therapeutic potential for type 1 diabetes is limited and depends on time-point of administration, choice of epitope and adjuvant. 1133 83

In NOD (nonobese diabetic) mice, a model of autoimmune diabetes, various immunomodulatory interventions prevent progression to diabetes. However, after hyperglycemia is established, such interventions rarely alter the course of disease or allow sustained engraftment of islet transplants. A proteasome defect in lymphoid cells of NOD mice impairs the presentation of self antigens and increases the susceptibility of these cells to TNF-alpha-induced apoptosis. Here, we examine the hypothesis that induction of TNF-alpha expression combined with reeducation of newly emerging T cells with self antigens can interrupt autoimmunity. Hyperglycemic NOD mice were treated with CFA to induce TNF-alpha expression and were exposed to functional complexes of MHC class I molecules and antigenic peptides either by repeated injection of MHC class I matched splenocytes or by transplantation of islets from nonautoimmune donors. Hyperglycemia was controlled in animals injected with splenocytes by administration of insulin or, more effectively, by implantation of encapsulated islets. These interventions reversed the established beta cell-directed autoimmunity and restored endogenous pancreatic islet function to such an extent that normoglycemia was maintained in up to 75% of animals after discontinuation of treatment and removal of islet transplants. A therapy aimed at the selective elimination of autoreactive cells and the reeducation of T cells, when combined with control of glycemia, is thus able to effect an apparent cure of established type 1 diabetes in the NOD mouse.
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PMID:Reversal of established autoimmune diabetes by restoration of endogenous beta cell function. 1143 53

Type 1 diabetes mellitus is strongly associated with HLA-DQ8 in humans and I-A(g7) in the NOD mouse. The disease is characterized by loss of tolerance to auto-antigens such as GAD, insulin, and the protein tyrosine phosphatase-like molecule, IA-2. We identified T cell epitopes on the intracytoplasmic region of IA-2 by immunizing DQ8/NOD, DQ8/B10, and NOD mice with overlapping 18 mer peptides in CFA. We identified four peptides presented both by DQ8 and NOD, five DQ8 specific peptides, and six NOD specific peptides. Both mouse lines failed to respond to ten peptides. We demonstrated MHC class II and CD4 restriction of proliferative responses using appropriate blocking antibodies. To understand the role of non-MHC genes in the generation of immune response to the islet auto-antigen, we evaluated cytokine secretion following immunization of DQ8 transgenic mice with strongly immunogenic peptides. The NOD background resulted in increased secretion of cytokines. In conclusion, we have identified IA-2 peptides that induce lymphoproliferative responses in DQ8 transgenic and NOD mice and shown that these peptides stimulate production of Th1 and Th2 cytokines.
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PMID:HLA-DQ8 transgenic and NOD mice recognize different epitopes within the cytoplasmic region of the tyrosine phosphatase-like molecule, IA-2. 1160 Feb 16

NKT cells are considered unconventional T cells. First, they are restricted by a nonclassical MHC class I molecule, CD1d, which presents glycolipids; second, their TCR repertoire is very limited. After stimulation by their TCR, NKT cells rapidly release large amounts of cytokines, such as IL-4 and IFN-gamma. Little is known about NKT cells present in lymph nodes. In the present report we show that NKT cells are differently distributed in various lymph nodes and are, for instance, abundant in pancreatic and mesenteric lymph nodes of C57BL/6 mice and nonobese diabetic mice. The high frequency of NKT cells in splanchnic lymph nodes is not simply a consequence of inflammatory signals, as draining lymph nodes still contain low frequencies of NKT cells after IFA or CFA injections. NKT cells from splanchnic lymph nodes harbor a Vbeta repertoire similar to that of splenic and liver NKT cells, in contrast to peripheral NKT cells that are not biased toward Vbeta8 segments. Analysis of cytokine production by NKT cells from splanchnic lymph nodes reveals that they produce at least as much IL-4 as IFN-gamma, in contrast to NKT cells from other organs (spleen, liver, and peripheral lymph nodes), which produce much more IFN-gamma than IL-4. These specific features of NKT cells from splanchnic lymph nodes might explain their protective action against the development of pathogenic Th1 cells in type 1 diabetes.
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PMID:Phenotypic and functional differences between NKT cells colonizing splanchnic and peripheral lymph nodes. 1190 79

We have established a novel CD4 and CD8 double-positive CD25+ T regulatory (Treg) clone, MT-5B, from lymph nodes of type 1 diabetes prone non-obese diabetic (NOD) mice immunized with CFA. CFA has previously been shown to prevent the onset of diabetes by inducing Treg cells. In vitro, clone MT-5B was anergic to a panel of antigen stimulations and exerted an immunosuppressive effect in antigen-non-specific and cell contact-independent manners. In vivo, clone MT-5B blocked the adoptive transfer of diabetes. Proteomics and immunoadsorption studies identified the suppressive proteins secreted by clone MT-5B as granzyme B (GrB) and perforin (PFN). GrB-mediated immune suppression was PFN dependent. Removal of GrB or PFN from the culture supernatant (SN) of MT-5B cells or pre-incubation of MT-5B cells with ethyleneglycol-bis(aminoethylether)-tetraacetic acid which blocks PFN activity reduced the immunosuppressive effect in vitro. Pre-incubation of diabetogenic splenocytes from NOD mice with MT-5B SN impaired their ability to transfer disease by inducing T cell apoptosis, and removal of GrB from MT-5B SN by immunoadsorption decreased the effector function of MT-5B SN on diabetogenic splenocytes. Immunization of NOD mice with CFA increased the expression of GrB+ CD4 T cells, indicating that these cells are present in vivo. In conclusion, we describe a novel mechanism of cell contact-independent immune suppression in which Treg cells maintain immune homeostasis by secreting GrB/PFN.
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PMID:A novel mechanism of regulatory T cell-mediated down-regulation of autoimmunity. 1667 87


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