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See detailThymic Expression of Insulin-Related Genes in an Animal Model of Autoimmune Type 1 Diabetes
Kecha-Kamoun, Ouafae; Achour, Imane; Martens, Henri ULg et al

in Diabetes/Metabolism Research & Reviews (2001), 17(2, Mar-Apr), 146-52

BACKGROUND: Insulin and multiple other autoantigens have been implicated in the pathogenesis of autoimmune type 1 diabetes, but the origin of immunological self-reactivity specifically oriented against ... [more ▼]

BACKGROUND: Insulin and multiple other autoantigens have been implicated in the pathogenesis of autoimmune type 1 diabetes, but the origin of immunological self-reactivity specifically oriented against insulin-secreting islet beta-cells remains obscure. The primary objective of the present study was to investigate the hypothesis that a defect in thymic central T-cell self-tolerance of the insulin hormone family could contribute to the pathophysiology of type 1 diabetes. This hypothesis was investigated in a classic animal model of type 1 diabetes, the Bio-Breeding (BB) rat. METHODS: The expression of the mammalian insulin-related genes (Ins, Igf1 and Igf2) was analysed in the thymus of inbred Wistar Furth rats (WF), diabetes-resistant BB (BBDR) and diabetes-prone BB (BBDP) rats. RESULTS: RT-PCR analyses of total RNA from WF, BBDP and BBDR thymi revealed that Igf1 and Ins mRNAs are present in 15/15 thymi from 2-day-old, 5-day-old and 5-week-old WF, BBDR and BBDP rats. In contrast, a complete absence of Igf2 mRNA was observed in more than 80% of BBDP thymi. The absence of detectable Igf2 transcripts in the thymus of BBDP rats is tissue-specific, since Igf2 mRNAs were detected in all BBDP brains and livers examined. Using a specific immunoradiometric assay, the concentration of thymic IGF-2 protein was significantly lower in BBDP than in BBDR rats (p<0.01). CONCLUSIONS: The present study suggests an association between the emergence of autoimmune diabetes and a defect in Igf2 expression in the thymus of BBDP rats. This tissue-specific defect in gene expression could contribute both to the lymphopenia of these rats (by impaired T-cell development) and the absence of central T-cell self-tolerance of the insulin hormone family (by defective negative selection of self-reactive T-cells). [less ▲]

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See detailCharacterization of the Insulin-Like Growth Factor Axis in the Human Thymus
Kecha, Ouafae; Martens, Henri ULg; Franchimont, Nathalie et al

in Journal of Neuroendocrinology (1999), 11(6), 435-40

The components of the insulin-like growth factor (IGF) axis have been investigated in the normal human thymus. Using ribonuclease protection assays (RPA), IGF-II transcripts were detected in the normal ... [more ▼]

The components of the insulin-like growth factor (IGF) axis have been investigated in the normal human thymus. Using ribonuclease protection assays (RPA), IGF-II transcripts were detected in the normal human thymus. By reverse transcriptase polymerase chain reaction (RT-PCR) analyses, promoters P3 and P4 were found to be active in the transcription of IGF2 gene within human thymic epithelial cells (TEC). No IGF-II mRNA could be detected in human lymphoid Jurkat T cells with 30 cycles of RT-PCR. By Northern blot analyses, IGFBP-2 to -6 (but not IGFBP-1) were found to be expressed in TEC with a predominance of IGFBP-4. Interestingly, Jurkat T cells only express IGFBP-2 but at high levels. The type 1 IGF receptor was detected in Jurkat T cells but not in human TEC. The identification of the components of the IGF axis within separate compartments of the human thymus adds further evidence for a role of this axis in the control of T-cell development. The precise influence of thymic IGF axis upon T-cell differentiation and immunological self-tolerance however needs to be further investigated. [less ▲]

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See detailCellular and molecular aspects of thymic T-cell education to neuroendocrine self principles: implications in autoimmunity
Geenen, Vincent ULg; Martens, Henri ULg; Kecha, Ouafae et al

in Annals of the New York Academy of Sciences (1998), 840

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See detailMolecular dissection of the insulin-like growth factor axis in the human thymus
Geenen, Vincent ULg; Kecha, Ouafae; Achour, Imane et al

in Diabetologia (1997), 40

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See detailCharacterization of the insulin-like growth (IGF) axis in the human thymus
Kecha, Ouafae; Achour, Imane; Martens, Henri ULg et al

in The Endocrine Society (Ed.) Proceedings of the 77th Annual Meeting of the Endocrine Society (1997)

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See detailDevelopmental and evolutionary aspects of thymic T-cell education to neuroendocrine self
Geenen, Vincent ULg; Benhida, Abdellah; Kecha, Ouafae et al

in Acta Haematologica (1996), 95

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See detailThymic insulin-like growth factors (IGFs) in man and in an animal model of autoimmune IDDM
Geenen, Vincent ULg; Achour, Imane; Kecha, Ouafae et al

in Diabetologia (1996), 39

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See detailCellular and molecular mechanisms involved in thymic T-cell education to neuroendocrine self principles
Geenen, Vincent ULg; Benhida, Abdellah; Kecha, Ouafae et al

in International Journal of Thymology (1996), 4

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See detailVieillissement, défenses immunitaires at axe somatotrope-facteurs de croissance apparentés à l'insuline
Kaiser, Marie-Joëlle ULg; Achour, Imane; Kecha, Ouafae et al

in Médecine et Hygiène (1995), 53

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See detailCryptocrine Signaling in the Thymus Network and T Cell Education to Neuroendocrine Self-Antigens
Geenen, Vincent ULg; Goxe, Béatrice; Martens, Henri ULg et al

in Journal of Molecular Medicine : Official Organ of the 'Gesellschaft Deutscher Naturforscher und Ärzte' (1995), 73(9), 449-55

Both during phylogeny and ontogeny the thymus appears as a nodal point between the two major systems of cell-to-cell signaling, the neuroendocrine and immune systems. This review presents the experimental ... [more ▼]

Both during phylogeny and ontogeny the thymus appears as a nodal point between the two major systems of cell-to-cell signaling, the neuroendocrine and immune systems. This review presents the experimental observations which support a dual role in T cell selection played by the thymic repertoire of neuroendocrine polypeptide precursors. Through the mode of cryptocrine intercellular signaling thymic neuroendocrine-related precursors synthesized in thymic epithelial cells have been shown to influence the early steps in T cell differentiation. In addition, thymic neuroendocrine-related polypeptides are a source of self-antigens which are presented by the major histocompatibility system of the thymic epithelium. Preliminary data also suggest that the intrathymic T cell education to neuroendocrine self-antigens is not strictly superimposible to the antigen presentation by dedicated presenting cells. Insulin-like growth factor-II (IGF-II) was identified as one dominant member of the insulin family expressed by thymic epithelial and nurse cells. The intrathymic presentation of IGF-II or IGF-II derived self-antigens is under current investigation. If further confirmed, the central tolerogenic properties of IGF-II could be considered in the elaboration of a strategy for an efficient and safe prevention of insulin-dependent diabetes. [less ▲]

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See detailLes choix stratégiques actuels dans la prévention du processus diabétogène auto-immun
Geenen, Vincent ULg; Martens, Henri ULg; Kecha, Ouafae et al

in Médecine et Hygiène (1994), 52

Le diabète insulino-dépendant (DID) est de plus en plus admis comme résultant d'une rupture de la tolérance immunitaire vis-à-vis de la cellule ß pancréatique. La compréhension des mécanismes centraux et ... [more ▼]

Le diabète insulino-dépendant (DID) est de plus en plus admis comme résultant d'une rupture de la tolérance immunitaire vis-à-vis de la cellule ß pancréatique. La compréhension des mécanismes centraux et périphériques de la tolérance vis-à-vis de la cellule ß doit logiquement aboutir à une prévention non toxique et efficace du DID. Deux choix stratégiques sont proposés à l'heure actuelle. D'une part, la tolérance périphérique à l'insuline en tant que cible du processus auto-immun pourrait être restaurée via l'administration d'insuline à faibles doses par voie sous-cutanée ou orale. D'autre part, le facteur de croissance apparenté à l'insuline de type 2 (IGF2) pourrait réinduire la tolérance centrale de l'insuline et, secondairement, de la cellule ß insulino-sécrétrice. [less ▲]

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See detailEvidence that insulin-like growth factor 2 (IGF2) is the dominant thymic peptide of the insulin superfamily
Geenen, Vincent ULg; Achour, Imane; Robert, Françoise et al

in Thymus (1993), 21(2), 115-127

Central T-cell tolerance of neurondocrine functions has been proposed to be primarily induced by the thymic repertoire of neuroendocrine self antigens. The present study aimed at characterizing the human ... [more ▼]

Central T-cell tolerance of neurondocrine functions has been proposed to be primarily induced by the thymic repertoire of neuroendocrine self antigens. The present study aimed at characterizing the human thymic insulin-related self antigen able to represent the pancreatic islet ß cell function in face of the developing T cells. Immunofluorescence studies were performed on human and rat thymic sections, as wess as on the rat IT-45R1 thymic epithelial cell line using several antibodies to epitopes of the insulin peptide family. These studies identify beyond any doubt that IGF2 is the dominant thymic peptide of the insulin family. The sequence of an insulin-derived autoantigen is proposed. This autoantigen is a nonamer and has a hydrophobic residue leucine at position 9. In human species, this autoantigen would primarily be tolerogenic for the pancreatic ß-cell endocrine function during fetal development. [less ▲]

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See detailEvidence that insulin-like growth factor 2 (IGF2) is the dominant thymic peptide of the insulin superfamily
Geenen, Vincent ULg; Achour, Imane; Martens, Henri ULg et al

in The Endocrine Society (Ed.) Proceedings of the 75th Annual Meeting of the Endocrine Society (1993)

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See detailThe thymic repertoire of neuroendocrine self antigens and the central immune tolerance of neuroendocrine functions
Geenen, Vincent ULg; Cormann, Nadine; Robert, Françoise et al

in European Journal of Medicine (The) (1992), 1(3), 158-165

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See detailLa communication cryptocrine et la reconnaissance des fonctions neuroendocrines par les cellules T au cours de leur différenciation
Geenen, Vincent ULg; Robert, Françoise; Martens, Henri ULg et al

in Revue Française d'Endocrinologie Clinique, Nutrition, et Métabolisme (La) (1992), 33

Le thymus, organe lymphoïde primaire responsable du développement des lymphocytes T, est le site d'expression de différents peptides appartenant à des familles hormonales distinctes. Le modèle classique ... [more ▼]

Le thymus, organe lymphoïde primaire responsable du développement des lymphocytes T, est le site d'expression de différents peptides appartenant à des familles hormonales distinctes. Le modèle classique de la neurosécrétion établi pour l'axe hypothalamo-neurohypophysaire ne peut cependant s'appliquer à la sécrétion de tels signaux par les cellules épithéliales thymiques. Un nouveau modèle de communication cellulaire, celui de la communication cryptocrine, a été proposé par John W. Funder pour décrire les échanges d'information entre une cellule épithéliale fixe et des cellules mobiles en différenciation à leur contact. Dans le thymus, la communication cryptocrine est étroitement associée à la présentation de la structure moléculaire du Soi par les molécules d'histocompatibilité (CMH) aux lymphocytes T au cours de leur différenciation. Sur la base de nos observations, le modèle du répertoire thymique des autoantigènes neuroendocrines permet de transposer au niveau moléculaire le double rôle physiologique du thymus dans les phénomènes de sélections négative et positive des cellules T, et d'apporter un éclairage nouveau sur les mécanismes responsables de la tolérance immunitaire centrale aux fonctions neuroendocrines. [less ▲]

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