An islet-homing NOD CD8+cytotoxic T cell clone recognizes GAD65and causes insulitis

Videbæk, Nicoline; Harach, Silvia Zusman; Phillips, Jenny; Hutchings, P; Ozegbe, Patricia; Michelsen, Birgitte; Cooke, Anne

doi:10.1016/s0896-8411(03)00003-9

Cited by 23 publications

(9 citation statements)

References 47 publications

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“…Recently, von Boehmer and colleagues (59) clearly demonstrated normal diabetes incidence in GAD Tg mice, despite complete tolerance to GAD. Furthermore, only one diabetogenic GAD 524 -543-specific CD4 ϩ T cell line, 5A, has been reported (60), and only one GADspecific CD8 ϩ clone causes insulitis, but not diabetes (61). In fact, a CD4…”

Section: Discussionmentioning

confidence: 99%

Diabetes Incidence Is Unaltered in Glutamate Decarboxylase 65-Specific TCR Retrogenic Nonobese Diabetic Mice: Generation by Retroviral-Mediated Stem Cell Gene Transfer

Arnold

Burton

Vignali

2004

The Journal of Immunology

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TCR transgenic mice are valuable tools for dissecting the role of autoantigen-specific T cells in the pathogenesis of type 1 diabetes but are time-consuming to generate and backcross onto congenic strains. To circumvent these limitations, we developed a new approach to rapidly generate mice expressing TCR using retroviral-mediated stem cell gene transfer and a novel picornavirus-like 2A peptide to link the TCR α- and β-chains in a single retroviral vector. We refer to these as retrogenic (Rg) mice to avoid confusion with conventional transgenic mice. Our approach was validated by demonstrating that Rg nonobese diabetic (NOD)-scid mice expressing the diabetogenic TCRs, BDC2.5 and 4.1, generate clonotype-positive T cells and develop diabetes. We then expressed three TCR specific for either glutamate decarboxylase (GAD) 206–220 or GAD 524–538 or for hen egg lysozyme 11–25 as a control in NOD, NOD-scid, and B6.H2g7 mice. Although T cells from these TCR Rg mice responded to their respective Ag in vitro, the GAD-specific T cells exhibited a naive, resting phenotype in vivo. However, T cells from Rg mice challenged with Ag in vivo became activated and developed into memory cells. Neither of the GAD-reactive TCR accelerated or protected mice from diabetes, nor did activated T cells transfer or protect against diabetes in NOD-scid recipients, suggesting that GAD may not be a primary target for diabetogenic T cells. Generation of autoantigen-specific TCR Rg mice represents a powerful approach for the analysis of a wide variety of autoantigens.

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Section: Discussionmentioning

confidence: 99%

Diabetes Incidence Is Unaltered in Glutamate Decarboxylase 65-Specific TCR Retrogenic Nonobese Diabetic Mice: Generation by Retroviral-Mediated Stem Cell Gene Transfer

Arnold

Burton

Vignali

2004

The Journal of Immunology

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“…Using immunization of NOD mice with GAD65 515-524 peptide, a GAD65 515-524 -specific clone was generated using the same approach (50). We first tested and compared the ability of both clones to proliferate in response to cognate and irrelevant peptides.…”

Section: Clone (See Materials and Methods)mentioning

confidence: 99%

Different Diabetogenic Potential of Autoaggressive CD8+ Clones Associated with IFN-γ-Inducible Protein 10 (CXC Chemokine Ligand 10) Production but Not Cytokine Expression, Cytolytic Activity, or Homing Characteristics

Ejrnæs

Videbæk²,

Christen

et al. 2005

The Journal of Immunology

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Type 1 diabetes mellitus is an autoimmune disease characterized by T cell-mediated destruction of the insulin-producing β cells in the islets of Langerhans. From studies in animal models, CD8+ T cells recognizing autoantigens such as islet-specific glucose-6-phosphatase catalytic subunit-related protein, insulin, or glutamic acid decarboxylase (GAD) are believed to play important roles in both the early and late phases of β cell destruction. In this study, we investigated the factors governing the diabetogenic potential of autoreactive CD8+ clones isolated from spleens of NOD mice that had been immunized with GAD65515–524 or insulin B-chain15–23 peptides. Although these two clones were identical in most phenotypic and functional aspects, for example cytokine production and killing of autologous β cells, they differed in the expression of IFN-γ-inducible protein-10, which was only produced at high levels by the insulin-specific clone, but not by the GAD65-specific clone, and other autoantigen-specific nonpathogenic CD8 T cell clones. Interestingly, upon i.p. injection into neonatal mice, only the insulin B-chain15–23-reactive CD8+ T clone accelerated diabetes in all recipients after 4 wk, although both insulin- and GAD-reactive clones homed to pancreas and pancreatic lymph nodes with similar kinetics. Diabetes was associated with increased pancreatic T cell infiltration and, in particular, recruitment of macrophages. Thus, secretion of IFN-γ-inducible protein-10 by autoaggressive CD8+ lymphocytes might determine their diabetogenic capacity by affecting recruitment of cells to the insulitic lesion.

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“…Although female and male NOD mice develop insulitis, females suffer more invasive and destructive insulitis, leading to a higher incidence of diabetes as compared with males. The development of autoimmune diabetes is T cell mediated and requires the participation of both CD4+ and CD8+ subsets [11].…”

Section: Introductionmentioning

confidence: 99%

Impact of Serum Granulocyte-Macrophage Colony-Stimulating Factor Levels among Diabetes Patients in Hilla City - Iraq

Al-Hassnawi¹,

Al-Thaheb²,

Al-Dahmoshi³

et al. 2014

als

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Background: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pro-inflammatory cytokine with growth factor-like properties for monocytes and dendritic cells. Methods: Study subjects were recruited from the hospital in Hilla city. Healthy controls (n=15) and D.M. patients (n=35) were included in the study. Serum levels of GM-CSF and Anti-Insulin Antibody (AIA) measured by using ELISA technique. Results: The serum GM-CSF levels were significantly higher among diabetes subjects as compared with subjects without diabetes and results showed a high significant in serum AIA and glucose levels in patient as compare with control (p=0.009, P=0.001). The serum GM-CSF levels were increased in age group (45-54 years) shows the higher percent (42.85%) of patients with diabetes, with decreased of AIA and GM-CSF level rather than other age groups. Conclusions: There is indirect relationship between AIA and GM-CSF level and that is mean increased AIA and glucose level reflect the reduced GM-CSF level among the diabetic patients may be used as biomarker or use GM-CSF as co-therapy with insulin.

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An islet-homing NOD CD8+cytotoxic T cell clone recognizes GAD65and causes insulitis

Cited by 23 publications

References 47 publications

Diabetes Incidence Is Unaltered in Glutamate Decarboxylase 65-Specific TCR Retrogenic Nonobese Diabetic Mice: Generation by Retroviral-Mediated Stem Cell Gene Transfer

Diabetes Incidence Is Unaltered in Glutamate Decarboxylase 65-Specific TCR Retrogenic Nonobese Diabetic Mice: Generation by Retroviral-Mediated Stem Cell Gene Transfer

Different Diabetogenic Potential of Autoaggressive CD8+ Clones Associated with IFN-γ-Inducible Protein 10 (CXC Chemokine Ligand 10) Production but Not Cytokine Expression, Cytolytic Activity, or Homing Characteristics

Impact of Serum Granulocyte-Macrophage Colony-Stimulating Factor Levels among Diabetes Patients in Hilla City - Iraq

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