Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice

Cooke, Anne; Mandel, T. E.

doi:10.1007/bf03347755

Cited by 346 publications

(548 citation statements)

References 31 publications

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“…We found that the production of IL-4 increased, whereas the production of IFN-γ decreased, indicating that the immunisation of NOD mice with rVV-GAD65 induced a Th2 immune response in an antigenspecific manner. Our finding is consistent with the results of previous reports on NOD mice treated with GAD protein systemically, nasally or orally [28,29,33,34,35] or vaccinated with GAD encoding plasmid DNA [41]. Th2 immune responses induced by rVV-GAD immunisation could play an important role in the prevention of autoimmune diabetes in this animal model.…”

Section: Discussionsupporting

confidence: 93%

“…In Type I diabetes, GAD and insulin have been identified as major autoantigens and tolerisation against these autoantigens has been attempted as a method for the prevention of the disease [14,32]. It has been reported that administration of purified GAD protein or peptide or insulin protein or peptide to NOD mice by a variety of routes can tolerise the T cell-mediated immune response against pancreatic beta cells, resulting in the prevention or delay of the development of insulitis and diabetes [28,29,33,34,35,36,37,38,39]. In many cases, the preventive effect was found to be associated with a Th2 shift [14,32].…”

Section: Discussionmentioning

confidence: 99%

“…Sera from NOD mice were collected 8 weeks after injection with 5×10 7 rVV-GAD65 or 5×10 7 rVV-MJ601 and reacted with recombinant human GAD65 protein (produced in baculovirus) as described elsewhere [28,29]. GAD65 protein was coated onto a 96-well microplate (10 µg/ml in 0.1 mol/l NaHCO 3 , pH 8.5) at 4°C overnight.…”

Section: Construction Of Recombinant Vaccinia Virus Expressing Mouse mentioning

confidence: 99%

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Prevention of autoimmune diabetes by immunogene therapy using recombinant vaccinia virus expressing glutamic acid decarboxylase

et al. 2002

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Aims/hypotheses. Type I (insulin-dependent) diabetes mellitus results from T-cell-mediated autoimmune destruction of pancreatic beta cells. Among the beta-cell autoantigens that have been implicated in triggering of beta-cell-specific autoimmunity, glutamic acid decarboxylase (GAD) is a strong candidate in both humans and the NOD mouse. We aimed to determine whether treatment with a recombinant vaccinia virus expressing GAD (rVV-GAD65) could prevent the development of diabetes in NOD mice. Methods. Three-eight-to-nine-week-old female NOD mice were injected with various doses of rVV-GAD65 or rVV-MJ601as a control. We then examined the incidence of diabetes, T-cell proliferative response to GAD, amounts of anti-GAD IgGs, cytokine production and generation of regulatory cell populations. Results. Administration of rVV-GAD65 to NOD mice prevented diabetes in an age-dependent and dose-dependent manner. Splenic T cells from rVV-GAD65-treated mice did not proliferate in response to GAD65.The amount of IgG1 was increased, whereas IgG2a amounts did not change in rVV-GAD65-treated NOD mice. The production of interleukin-4 increased, whereas the production of interferon-γ decreased in rVV-GAD65-treated mice after stimulation with GAD. Furthermore, splenocytes from rVV-GAD65-treated NOD mice prevented the transfer of diabetes by splenocytes from acutely diabetic NOD mice in NOD.scid recipients. Conclusion/interpretation. Immunogene therapy using a recombinant vaccinia virus expressing GAD results in the prevention of autoimmune diabetes in NOD mice by the induction of immunological tolerance through active suppression of effector T cells, and this treatment might have therapeutic value for the prevention of Type I diabetes. [Diabetologia (2002)

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Construction Of Recombinant Vaccinia Virus Expressing Mouse mentioning

confidence: 99%

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Prevention of autoimmune diabetes by immunogene therapy using recombinant vaccinia virus expressing glutamic acid decarboxylase

et al. 2002

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“…With the onset of periinsulitis, beta-cell-antigenspecific T cells become detectable [25,32,33]. These islet-specific T cells are of TH1 phenotype and show signs of activation [33,34].…”

Section: Discussionmentioning

confidence: 99%

Pancreatic NOD beta cells express MHC class II protein and the frequency of I-Ag7 mRNA-expressing beta cells strongly increases during progression to autoimmune diabetes

et al. 2003

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Aims/hypothesis. In the NOD mouse model, attempts to show MHC class II expression by pancreatic beta cells were unsuccessful so far. We readdressed this question by analysing I-A g7 expression in single pancreatic beta cells. Methods. Single-cell multiplex RT PCR and singlecell immunofluorescence were used to study MHC class II expression in NOD and NOD/SCID beta cells. Results. Pancreatic beta cells from NOD mice express the I-A g7 protein as well as the corresponding mRNA. The frequency of MHC class II mRNA-expressing beta cells is drastically increased during the progression to overt diabetes. MHC class II protein is accumulated intracellularly, and invariant chain is co-expressed.

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“…10 The initial autoimmunity to GAD65 triggers a spreading T-cell response to other pancreatic b-cell antigens; importantly, tolerance induction to GAD65 can block the spreading to other b-cell antigens, thus preventing diabetes. 12,13 In this study, a retroviral construct encoding full-length pathogenic murine GAD65 at the N-terminus of murine IgG scaffold was used to treat NOD mice by delivering retrovirally genetransfected LPS-stimulated splenocytes. Herein, we demonstrate that GAD-IgG fusion construct could induce significant antigen-specific hyporesponsiveness at both cellular and humoral levels, and protect against the onset of diabetes in NOD mice.…”

Section: Introductionmentioning

confidence: 99%

Retroviral delivery of GAD-IgG fusion construct induces tolerance and modulates diabetes: a role for CD4+ regulatory T cells and TGF-β?

Song¹,

Wang²,

Wang³

et al. 2004

Gene Ther

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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 À 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-b 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-b.

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Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice

Cited by 346 publications

References 31 publications

Prevention of autoimmune diabetes by immunogene therapy using recombinant vaccinia virus expressing glutamic acid decarboxylase

Prevention of autoimmune diabetes by immunogene therapy using recombinant vaccinia virus expressing glutamic acid decarboxylase

Pancreatic NOD beta cells express MHC class II protein and the frequency of I-Ag7 mRNA-expressing beta cells strongly increases during progression to autoimmune diabetes

Retroviral delivery of GAD-IgG fusion construct induces tolerance and modulates diabetes: a role for CD4+ regulatory T cells and TGF-β?

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