Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have demonstrated that antigen-specific tolerance could be induced by lipopolysaccharide (LPS)-stimulated B cells retrovirally transduced with an immunoglobulin-antigen (or epitope-containing peptide) fusion construct. To investigate the mechanism of this gene therapy system, we now adapted this approach to immunotherapy of spontaneous diabetes in nonobese diabetic (NOD) mice, a T-cell-mediated autoimmune disease triggered, in part, by a pathogenic response to glutamate decarboxylase (GAD) 65. We demonstrate that LPS-stimulated splenocytes, retrovirally transfected with GAD-IgG fusion construct, induce a significant antigen-specific hyporesponsiveness at both cellular and humoral levels and reduce the incidence of diabetes in female NOD mice. Parallel with disease protection, we observed a prolonged increase of the numbers of CD4+CD25+ T cells in the periphery of GAD-IgG-treated mice, compared to those treated with a control IgG vector, both in the prediabetic period and persisting even 8 months after gene therapy. This increase appeared to be induced by the repeated stimulation of the antigen in the periphery instead of a result of differentiation of T-cell precursor in the thymus. Moreover, CD4+CD25+ T cells induced by GAD-IgG fusion construct were capable of suppressing the proliferative response of CD4+CD25- T cells in vitro; and ablation of the activity of CD4+CD25+ T cells by blocking antibody against CD25 could reverse GAD-specific T-cell hyporesponsiveness. These results suggested that CD4+CD25+ T-cell subset induced in GAD-IgG-treated NOD mice represented the regulatory or suppressive CD4+CD25+ T cells (Treg) and might play an important role in the induction and maintenance of tolerance in NOD mice. Furthermore, the numbers of splenic CD4+CD62L+ regulatory T cells in GAD-IgG-treated mice during the prediabetic period and serum TGF-beta levels in 34-38-week-old GAD-IgG-protected mice were also increased, compared to control IgG-treated ones. Therefore, we propose that the induction of tolerance and the prevention of diabetes incidence in NOD female mice induced by the GAD-IgG fusion construct may require CD4+ regulatory T cells, and the possible mediation of TGF-beta.
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PMID:Retroviral delivery of GAD-IgG fusion construct induces tolerance and modulates diabetes: a role for CD4+ regulatory T cells and TGF-beta? 1534 60

Phenotypically "immature" dendritic cells (DCs), defined by low cell surface CD40, CD80, and CD86 can elicit host immune suppression in allotransplantation and autoimmunity. Herein, we report the most direct means of achieving phenotypic immaturity in NOD bone marrow-derived DCs aiming at preventing diabetes in syngeneic recipients. CD40, CD80, and CD86 cell surface molecules were specifically down-regulated by treating NOD DCs ex vivo with a mixture of antisense oligonucleotides targeting the CD40, CD80, and CD86 primary transcripts. The incidence of diabetes was significantly delayed by a single injection of the engineered NOD DCs into syngeneic recipients. Insulitis was absent in diabetes-free recipients and their splenic T cells proliferated in response to alloantigen. Engineered DC promoted an increased prevalence of CD4(+)CD25(+) T cells in NOD recipients at all ages examined and diabetes-free recipients exhibited significantly greater numbers of CD4(+)CD25(+) T cells compared with untreated NOD mice. In NOD-scid recipients, antisense-treated NOD DC promoted an increased prevalence of these putative regulatory T cells. Collectively, these data demonstrate that direct interference of cell surface expression of the major costimulatory molecules at the transcriptional level confers diabetes protection by promoting, in part, the proliferation and/or survival of regulatory T cells. This approach is a useful tool by which DC-mediated activation of regulatory T cells can be studied as well as a potential therapeutic option for type 1 diabetes.
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PMID:Antisense oligonucleotides down-regulating costimulation confer diabetes-preventive properties to nonobese diabetic mouse dendritic cells. 1538 62

Activation-induced cell death (AICD) plays a key role in the homeostasis of the immune system. Autoreactive T cells are eliminated through AICD both from the thymus and periphery. In this study, we show that NOD peripheral T cells, especially CD8(+) T cells, display a decreased susceptibility to anti-CD3-induced AICD in vivo compared with T cells from diabetes-resistant B6, nonobese diabetes-resistant, and NOD.B6Idd4 mice. The susceptibility of NOD CD8(+) T cells to AICD varies in an age- and dose-dependent manner upon stimulation in vivo with either a mitogenic or nonmitogenic anti-CD3. NOD T cells preactivated by anti-CD3 in vivo are less susceptible than B6 T cells to TCR-induced AICD. Treatment of NOD mice with a mitogenic anti-CD3 depletes CD4(+)CD25(-)CD62L(+) but not CD4(+)CD25(+)CD62L(+) T cells, thereby resulting in an increase of the latter subset in the spleen. Treatment with a nonmitogenic anti-CD3 mAb delays the onset of T1D in 8.3 TCR transgenic NOD mice. These results demonstrate that the capacity of anti-CD3 to protect NOD mice from T1D correlates with its ability to perturb T cell homeostasis by inducing CD8(+) T cell AICD and increasing the number of CD4(+)CD25(+)CD62L(+) T cells in the periphery.
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PMID:Perturbed homeostasis of peripheral T cells elicits decreased susceptibility to anti-CD3-induced apoptosis in prediabetic nonobese diabetic mice. 1538 71

Evidence suggests that steroid sparing in renal transplantation is associated with good outcomes, although there are limited data regarding steroid sparing in Tacrolimus and Mycophenolate Mofetil (MMF)-based regimes. In this study we describe the use of these agents in 101 consecutive patients undergoing renal transplantation using only a 7-day course of prednisolone. Median follow-up was 33 months (range 18-44). Patient and graft survival at 1 year were 100% and 98%, respectively. The acute rejection rate at both 6 and 12 months was 19%, with two episodes beyond 12 months. Anti-CD25 monoclonal antibody (anti-CD25 mAb) was administered to 25 patients at high immunological risk: a trend toward a lower rejection rate was seen in these patients compared with those at lower risk but not receiving induction therapy (8% vs. 22%; p = 0.11). Two patients experienced recurrent rejection. Of the twenty-three rejection episodes in total, 26% showed vascular involvement. Allograft function was preserved at 12 months with a mean creatinine of 144 micromol/L and mean estimated glomerular filtration rate (GFR) of 55 mL/min. At 12 months, the incidence of post-transplant diabetes mellitus was 3.5%. This steroid-sparing regime is associated with excellent patient and graft outcomes, and a low incidence of side effects.
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PMID:Steroid sparing with tacrolimus and mycophenolate mofetil in renal transplantation. 1547 85

CD4+ CD25+ T cells are a population of regulatory T cells responsible for active suppression of autoimmunity. Specifically, CD4+ CD25+ T cells have been shown to prevent insulin-dependent diabetes mellitus, inflammatory bowel disease, and pancreatitis. Here, we present evidence that CD4+ CD25+ T cells also play a major role in controlling the severity of arthritis detected in Borrelia burgdorferi-vaccinated gamma interferon-deficient (IFN-gamma degrees ) C57BL/6 mice challenged with the Lyme spirochete. When B. burgdorferi-vaccinated and challenged IFN-gamma degrees mice were treated with anti-interleukin-17 (IL-17) antibody, the number of CD4+ CD25+ T cells increased in the local lymph nodes. Furthermore, histopathologic examination showed the mice to be free of destructive arthritis. When these anti-IL-17-treated B. burgdorferi-vaccinated and challenged mice were also administered anti-CD25 antibody, the number of CD4+ CD25+ T cells in the local lymph nodes decreased. More importantly, severe destructive arthropathy was induced. In addition, delayed administration of anti-CD25 antibody decreased the severity of the arthritis. These results suggest that CD4+ CD25+ T cells are involved in regulation of a severe destructive arthritis induced with an experimental model of vaccination and challenge with B. burgdorferi.
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PMID:Association of CD4+ CD25+ T cells with prevention of severe destructive arthritis in Borrelia burgdorferi-vaccinated and challenged gamma interferon-deficient mice treated with anti-interleukin-17 antibody. 1553 9

Autoimmunity presumably manifests as a consequence of a shortfall in the maintenance of peripheral tolerance by CD4(+)CD25(+) T regulatory cells (Tregs). However, the mechanism underlying the functional impairment of Tregs remains largely undefined. In this study a glutamic acid decarboxylase (GAD) diabetogenic epitope was expressed on an Ig to enhance tolerogenic function, and the resulting Ig-GAD expanded Tregs in both young and older insulitis-positive, nonobese diabetic (NOD) mice, but delayed autoimmune diabetes only in the former. Interestingly, Tregs induced at 4 wk of age had significant active membrane-bound TGF-beta (mTGF-beta) and sustained protection against diabetes, whereas Tregs expanded during insulitis had minimal mTGF-beta and could not protect against diabetes. The Tregs probably operate suppressive function through mTGF-beta, because Ab blockade of mTGF-beta nullifies protection against diabetes. Surprisingly, young Tregs that modulated pathogenic T cells maintained stable frequency over time in the protected animals, but decreased their mTGF-beta at the age of 8 wk. More strikingly, these 8-wk-old mTGF-beta-negative Tregs, which were previously protective, became unable to confer resistance against diabetes. Thus, a developmental decline in active mTGF-beta nullifies Treg function, leading to a break in tolerance and the onset of diabetes.
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PMID:A sudden decline in active membrane-bound TGF-beta impairs both T regulatory cell function and protection against autoimmune diabetes. 1558 54

CD4(+)CD25(+) T-cells can be used to interfere with spontaneous autoimmune diseases such as type 1 diabetes. However, their low frequency and often unknown specificity represent major obstacles to their therapeutic use. Here we have explored the fact that ectopic expression of the transcription factor Foxp3 can confer a suppressor phenotype to naive CD4(+) T-cells. We found that retroviral transduction of polyclonal CD4 T-cells with FoxP3 was not effective in interfering with established type 1 diabetes. Thus, more subtle and more organ-specific regulation might be required to prevent type 1 diabetes, as well as to avoid systemic immunosuppression. However, a single injection of 10(5) FoxP3-transduced T-cells with specificity for islet antigen stabilized and reversed disease in mice with recent-onset diabetes. By comparing FoxP3-transduced T-cells with various antigen specificities, it became clear that the in vivo effect correlated with specific homing to and activation in pancreatic lymph nodes and not with in vitro suppressor activity or cytokine production. Our results complement recent results on in vitro-amplified antigen-specific T-cells in ameliorating type 1 diabetes and suggest that FoxP3 transduction of expanded T-cells might achieve the same goal.
Diabetes 2005 Feb
PMID:Antigen-specific FoxP3-transduced T-cells can control established type 1 diabetes. 1559 38

Accumulating evidence that granulocyte colony-stimulating factor (G-CSF), the key hematopoietic growth factor of the myeloid lineage, not only represents a major component of the endogenous response to infections, but also affects adaptive immune responses, prompted us to investigate the therapeutic potential of G-CSF in autoimmune type 1 diabetes. Treatment with G-CSF protected NOD mice from developing spontaneous diabetes. G-CSF triggered marked recruitment of dendritic cells (DCs), particularly immature CD11c(lo)B220(+) plasmacytoid DCs, with reduced costimulatory signal expression and higher interferon-alpha but lower interleukin-12p70 release capacity than DCs in excipient-treated mice. G-CSF recipients further displayed accumulation of functional CD4(+)CD25(+) regulatory T-cells that produce transforming growth factor-beta1 (TGF-beta1) and actively suppressed diabetes transfer by diabetogenic effector cells in secondary NOD-SCID recipients. G-CSF's ability to promote key tolerogenic interactions between DCs and regulatory T-cells was demonstrated by enhanced recruitment of TGF-beta1-expressing CD4(+)CD25(+) cells after adoptive transfer of DCs isolated from G-CSF- relative to vehicle-treated mice into naive NOD recipients. The present results suggest that G-CSF, a promoter of tolerogenic DCs, may be evaluated for the treatment of human type 1 diabetes, possibly in association with direct inhibitors of T-cell activation. They also provide a rationale for a protective role of the endogenous G-CSF produced during infections in early diabetes.
Diabetes 2005 Jan
PMID:Treatment with granulocyte colony-stimulating factor prevents diabetes in NOD mice by recruiting plasmacytoid dendritic cells and functional CD4(+)CD25(+) regulatory T-cells. 1561 13

Type 1 diabetes is a T-cell-mediated disease that is associated with loss of immunological tolerance to self-antigens. The mechanisms involved in maintenance of peripheral tolerance include a specialized subset of regulatory T-cells (Treg) within the CD4(+)CD25(+) T-cell population, but the function and phenotype of these cells in type 1 diabetes have not been investigated. We hypothesized that a deficiency in the CD4(+)CD25(+) Treg population or its function could contribute to the lack of self-tolerance evident in patients with type 1 diabetes. We show that although levels of CD4(+)CD25(+) T-cells are normal in patients with recent-onset adult type 1 diabetes, the ability of the Tregs in this population to suppress T-cell proliferation during in vitro cocultures is markedly reduced compared with control subjects (P = 0.007). Moreover, in patients with type 1 diabetes, these cocultures display a more proinflammatory phenotype, with increased secretion of interferon-gamma (P = 0.005) and decreased interleukin-10 production (P = 0.03). These deficiencies may reflect a disturbance in the balance of the CD4(+)CD25(+) population, because in patients with type 1 diabetes, a higher proportion of these cells coexpress the early activation marker CD69 (P = 0.007) and intracellular CTLA-4 (P = 0.01). These data demonstrate deficiency in function of the CD4(+)CD25(+) Treg population that may influence the pathogenesis of type 1 diabetes.
Diabetes 2005 Jan
PMID:Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes. 1561 15

Little is known about the pathogenic role of B cell dysfunction in T cell-mediated autoimmune disease. We previously reported that B cell hyper-responsiveness, resistance to apoptosis, and accumulation in islets occur during the onset of insulitis, but not in type 1 diabetes (T1D), in NOD mice. In this study we extended these studies to further determine how islet-infiltrated B cells contribute to this inflammatory insulitis. We demonstrate the presence of an increased percentage of B7-1(+) and a decreased percentage of B7-2(+) B cells in the spleen of autoimmune disease-prone NOD and nonobese diabetes-resistant mice compared with the spleen of nonautoimmune disease-prone C57BL/6 and BALB/c mice. An age-dependent differential expression of B7-1 and B7-2 was associated with the development of insulitis and CD4(+)CD25(+) T cell deficiency in autoimmune disease-prone mice. Whereas BCR and LPS stimulation increased B7-2 expression on B cells from autoimmune disease-prone and nonautoimmune disease-prone mice, LPS-induced B7-1 expression was higher on NOD than C57BL/6 B cells. Interestingly, increased expression of B7-1 and B7-2 was found on islet-infiltrated B cells, and this increase was associated with enhanced T cell costimulation. Islet-infiltrated B cells were shown to be a source of TNF-alpha production in islets. B7 blockade of BCR-stimulated NOD B cells by anti-B7-1 and anti-B7-2 mAbs during coadoptive transfer with diabetogenic T cells into NOD.scid mice protected these recipients from T1D. These results suggest that increased B7-1 and B7-2 expression on islet-infiltrated NOD B cells is associated with increased T cell costimulation and the development of inflammatory insulitis in NOD mice.
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PMID:Dysregulated B7-1 and B7-2 expression on nonobese diabetic mouse B cells is associated with increased T cell costimulation and the development of insulitis. 1563 86


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