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See detailThymic self-antigens for the design of a negative/tolerogenic self-vaccination against type 1 diabetes.
Geenen, Vincent ULg; Mottet, Marie ULg; Dardenne, Olivier ULg et al

in Current Opinion in Pharmacology (2010), 10

Before being able to react against infectious non-self antigens, the immune system has to be educated in the recognition and tolerance of neuroendocrine proteins and this critical process takes place only ... [more ▼]

Before being able to react against infectious non-self antigens, the immune system has to be educated in the recognition and tolerance of neuroendocrine proteins and this critical process takes place only in the thymus. The development of the autoimmune diabetogenic response results from a thymus dysfunction in programming central self-tolerance to pancreatic insulin-secreting islet β cells, leading to the breakdown of immune homeostasis with an enrichment of islet β-cell reactive effector T cells and a deficiency of β-cell specific natural regulatory T cells (nTregs) in the peripheral T-lymphocyte repertoire. Insulin-like growth factor 2 (IGF-2) is the dominant member of the insulin family expressed during fetal life by the thymic epithelium under the control of the autoimmune regulator (AIRE) gene/protein. The very low degree of insulin gene transcription in normal murine and human thymus explains why the insulin protein is poorly tolerogenic as evidenced in many studies, including the failure of all clinical trials that have attempted immune tolerance to islet β cells via various methods of insulin administration. Based on the close homology and cross-tolerance between insulin, the primary T1D autoantigen, and IGF-2, the dominant self-antigen of the insulin family, a novel type of vaccination, so-called “negative/tolerogenic self-vaccination”, is currently being developed for prevention and cure of T1D. If this approach were found to be effective for reprogramming immunological tolerance in T1D, it could pave the way for the design of other self-vaccines against autoimmune endocrine diseases, as well as other organ-specific autoimmune diseases. [less ▲]

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See detailTranscriptomic biomarkers of the response of hospitalized geriatric patients with infectious diseases
Duy Vo, Thi Kim; Godard, Patrice; de Saint-Hubert, Marie et al

in Immunity & Ageing : I & A (2010), 17

Background: Infectious diseases are significant causes of morbidity and mortality among elderly populations. However, the relationship between oxidative stress, immune function and inflammatory response ... [more ▼]

Background: Infectious diseases are significant causes of morbidity and mortality among elderly populations. However, the relationship between oxidative stress, immune function and inflammatory response in acute phase of the infectious disease is poorly understood. Results: Herein the abundance of a selection of 148 transcripts involved in immunosenescence and stress response was compared in total RNA of PBMC of 28 healthy aged probands and 39 aged patients in acute phase of infectious disease (day 2-4 after hospitalization) or in convalescence phase (day 7-10). This study provides a list of 24 differentially abundant transcript species in the acute phase versus healthy aged. For instance, transcripts associated with inflammatory and anti-inflammatory reactions (TNFRSF1A, IL1R1, IL1R2, IL10RB) and with oxidative stress (HMOX1, GPX1, SOD2, PRDX6) were more abundant while those associated with T-cell functions (CD28, CD69, LCK) were less abundant in acute phase. The abundance of seven of these transcripts (CD28, CD69, LCK, CTSD, HMOX1, TNFRSF1A and PRDX6) was already known to be altered in healthy aged probands compared to healthy young ones and was further affected in aged patients in acute phase, compromising an efficient response. Conclusion: This work provides insights of the state of acute phase response to infections in elderly patients and could explain further the lack of appropriate response in the elderly compared to younger persons. [less ▲]

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See detailImpact of growth hormone (GH) deficiency and GH replacement upon thymus function in adult patients.
Morrhaye, Gabriel ULg; Kermani, Hamid; Legros, Jean-Jacques ULg et al

in PLoS ONE (2009), 4(5), 5668

BACKGROUND: Despite age-related adipose involution, T cell generation in the thymus (thymopoiesis) is maintained beyond puberty in adults. In rodents, growth hormone (GH), insulin-like growth factor-1 ... [more ▼]

BACKGROUND: Despite age-related adipose involution, T cell generation in the thymus (thymopoiesis) is maintained beyond puberty in adults. In rodents, growth hormone (GH), insulin-like growth factor-1 (IGF-1), and GH secretagogues reverse age-related changes in thymus cytoarchitecture and increase thymopoiesis. GH administration also enhances thymic mass and function in HIV-infected patients. Until now, thymic function has not been investigated in adult GH deficiency (AGHD). The objective of this clinical study was to evaluate thymic function in AGHD, as well as the repercussion upon thymopoiesis of GH treatment for restoration of GH/IGF-1 physiological levels. METHODOLOGY/PRINCIPAL FINDINGS: Twenty-two patients with documented AGHD were enrolled in this study. The following parameters were measured: plasma IGF-1 concentrations, signal-joint T-cell receptor excision circle (sjTREC) frequency, and sj/beta TREC ratio. Analyses were performed at three time points: firstly on GH treatment at maintenance dose, secondly one month after GH withdrawal, and thirdly one month after GH resumption. After 1-month interruption of GH treatment, both plasma IGF-1 concentrations and sjTREC frequency were decreased (p<0.001). Decreases in IGF-1 and sjTREC levels were correlated (r = 0.61, p<0.01). There was also a decrease in intrathymic T cell proliferation as indicated by the reduced sj/beta TREC ratio (p<0.01). One month after reintroduction of GH treatment, IGF-1 concentration and sjTREC frequency regained a level equivalent to the one before GH withdrawal. The sj/beta TREC ratio also increased with GH resumption, but did not return to the level measured before GH withdrawal. CONCLUSIONS: In patients with AGHD under GH treatment, GH withdrawal decreases thymic T cell output, as well as intrathymic T cell proliferation. These parameters of thymus function are completely or partially restored one month after GH resumption. These data indicate that the functional integrity of the somatotrope GH/IGF-1 axis is important for the maintenance of a normal thymus function in human adults. TRIAL REGISTRATION: ClinicalTrials.gov NTC00601419. [less ▲]

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See detailAire and Foxp3 expression in a particular microenvironment for T-cell differentiation
Hansenne, Isabelle; Louis, Céline; Martens, Henri ULg et al

in Neuroimmunomodulation (2009), 16

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See detailIntegrity of the somatotrope GH/IGF-1 axis is required for normal thymus function: a clinical study in patients with adult GH deficiency
Morrhaye, Gabriel ULg; Kermani, Hamid; Cheynier, Rémi et al

in The Endocrine Society (Ed.) Proceedings of the 2009 Annual Meeting of the Endocrine Society (2009)

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See detailEvaluation clinique de la fonction du thymus.
Castermans, Emilie ULg; Morrhaye, Gabriel ULg; Marchand, S. et al

in Revue Médicale de Liège (2007), 62(11), 675-8

The essential role of the thymus is to install an extremely diverse repertoire of T lymphocytes that are self-tolerant and competent against non-self, as well as to generate self-antigen specific ... [more ▼]

The essential role of the thymus is to install an extremely diverse repertoire of T lymphocytes that are self-tolerant and competent against non-self, as well as to generate self-antigen specific regulatory T cells (Treg) able to inactivate in periphery self-reactive T cells having escaped the thymic censorship. Although indirect, techniques of medical imaging and phenotyping of peripheral T cells may help in the investigation of thymic function. Nowadays however, thymopoiesis is better evaluated through quantification by PCR of T-cell receptor excision circles (TREC) generated by intrathymic random recombination of the gene segments coding for the variable parts of the T-cell receptor for antigen (TCR). The TREC methodology is very valuable in the circumstances not associated with intense proliferation or apoptosis of peripheral T lymphocytes. [less ▲]

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See detailEvaluation de la thymopoiese: applications cliniques.
Castermans, Emilie ULg; Morrhaye, Gabriel ULg; Marchand, S. et al

in Revue Médicale de Liège (2007), 62(12), 725-9

In the precedent article, we have described how T-cell generation in the thymus (thymopoiesis) may be currently evaluated through quantification by PCR of T-cell receptor excision circles (TREC) generated ... [more ▼]

In the precedent article, we have described how T-cell generation in the thymus (thymopoiesis) may be currently evaluated through quantification by PCR of T-cell receptor excision circles (TREC) generated by intrathymic random recombination of the gene segments coding for variable parts of T-cell receptor for antigen (TCR). In hematology, TREC methodology helps in a better understanding of immune reconstitution after graft of hematopoietic stem cells: first there is a proliferation of mature T cells present in the graft, then a differentiation of naive T cells. In geriatrics, the homeostasis of the peripheral T-cell repertoire is maintained through proliferation of peripheral memory T cells rather than through thymic generation of naive T cells. In addition, TREC quantification constitutes a novel major tool for deciphering the tight control of thymopoiesis by the neuroendocrine system. [less ▲]

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See detailNouvelles donnees sur la pathogenie du diabete de type 1
Geenen, Vincent ULg; Brilot, F.; Louis, Céline ULg et al

in Revue Médicale de Liège (2005), 60(5-6, May-Jun), 291-6

The autoimmune nature of the diabetogenic process and the major contribution of T lymphocytes stand now beyond any doubt. However, despite the identification of the three major type 1-diabetes-related ... [more ▼]

The autoimmune nature of the diabetogenic process and the major contribution of T lymphocytes stand now beyond any doubt. However, despite the identification of the three major type 1-diabetes-related autoantigens (insulin, GAD65 and phosphatase IA-2), the origin of this immune dysregulation still remains unknown. More and more evidence supports a thymic dysfunction in the establishment of central self-tolerance to the insulin family as a crucial factor in the development of the autoimmune response selective of pancreatic insulin-secreting islet beta cells. All the genes of the insulin family (INS, IGF1 and IGF2) are expressed in the thymus network. However, IGF-2 is the dominant member of this family first encountered by T cells in the thymus, and only IGFs control early T-cell differentiation. IGF2 transcription is defective in the thymus in one animal model of type 1 diabetes, the Bio-Breeding (BB) rat. The sequence B9-23, one dominant autoantigen of insulin, and the homologous sequence B11-25 derived from IGF-2 exibit the same affinity and fully compete for binding to DQ8, one class-II major histocompatibility complex (MHC-II) conferring major genetic susceptibility to type 1 diabetes. Compared to insulin B9-23, the presentation of IGF-2 B11-25 to peripheral mononuclear cells (PBMCs) isolated from type 1 diabetic DQ8+ adolescents elicits a regulatory/tolerogenic cytokine profile (*IL-10, *IL-10/IFN-g, *IL-4). Thus, administration of IGF-2 derived self-antigen(s) might constitute a novel form of vaccine/immunotherapy combining both an antagonism for the site of presentation of a susceptible MHC allele, as well as a downstream tolerogenic/regulatory immune response. [less ▲]

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See detailAn insulin-like growth factor 2-derived self-antigen inducing a regulatory cytokine profile after presentation to peripheral blood mononuclear cells from DQ8(+) type 1 diabetic adolescents - Preliminary design of a thymus-based tolerogenic self-vaccination
Geenen, Vincent ULg; Louis, Céline ULg; Martens, Henri ULg

in Annals of the New York Academy of Sciences (2004), 1037

This work aims to evaluate the potential use of insulin-like growth factor 2 (IGF-2) as the dominant thymic self-antigen precursor of the insulin family in designing a tolerogenic approach to type 1 ... [more ▼]

This work aims to evaluate the potential use of insulin-like growth factor 2 (IGF-2) as the dominant thymic self-antigen precursor of the insulin family in designing a tolerogenic approach to type 1 diabetes (T1D) prevention. This evaluation was primarily based on cytokine profile driven by MHC presentation of insulin and IGF-2-derived antigens to PBMC cultures derived from 16 T1D DQ8(+) adolescents. Insulin B9-23, one dominant P-cell autoantigen, and the homologous sequence B11-25 of IGF-2 display the same affinity and fully compete for binding to DQ8, a MHC-II allele conferring major genetic susceptibility to type 1 diabetes (T1D). However, compared to insulin beta 9-23, presentation of IGF-2 B11-25 elicits a suppressive/regulatory cytokine profile with a higher number of IL-10-secreting cells (P < 0.05), a much higher ratio of IL-10/IFN-gamma (P < 0.01), as well as a lower number of IL-4-secreting cells (P < 0.05). Thus, with regard to T1D prevention, administration of IGF-2-derived self-antigen(s) seems to be an efficient approach that combines both antagonism for binding to a major susceptibility MHC-II allele, as well as downstream promotion of an antigen-driven tolerogenic response. [less ▲]

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See detailNeurohypophysial Receptor Gene Expression by Thymic T Cell Subsets and Thymic T Cell Lymphoma Cell Lines
Hansenne, Isabelle ULg; Rasier, G.; Charlet-Renard, C. et al

in Clinical & Developmental Immunology (2004), 11(1), 45-51

Neurohypophysial oxytocin (OT) and vasopressin (VP) genes are transcribed in thymic epithelium, while immature T lymphocytes express functional neurohypophysial receptors. Neurohypophysial receptors ... [more ▼]

Neurohypophysial oxytocin (OT) and vasopressin (VP) genes are transcribed in thymic epithelium, while immature T lymphocytes express functional neurohypophysial receptors. Neurohypophysial receptors belong to the G protein-linked seven-transmembrane receptor superfamily and are encoded by four distinct genes, OTR, V1R, V2R and V3R. The objective of this study was to identify the nature of neurohypophysial receptor in thymic T cell subsets purified by immunomagnetic selection, as well as in murine thymic lymphoma cell lines RL12-NP and BW5147. OTR is transcribed in all thymic T cell subsets and T cell lines, while V3R transcription is restricted to CD4+CD8+ and CD8+ thymic cells. Neither V1R nor V2R transcripts are detected in any kind of T cells. The OTR protein was identified by immunocytochemistry on thymocytes freshly isolated from C57BL/6 mice. In murine fetal thymic organ cultures, a specific OTR antagonist does not modify the percentage of T cell subsets, but increases late T cell apoptosis further evidencing the involvement of OT/OTR signaling in the control of T cell proliferation and survival. According to these data, OTR and V3R are differentially expressed during T cell ontogeny. Moreover, the restriction of OTR transcription to T cell lines derived from thymic lymphomas may be important in the context of T cell leukemia pathogenesis and treatment. [less ▲]

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See detailPresentation of neuroendocrine self in the thymus: toward a novel type of vaccine/immunotherapy
Geenen, Vincent ULg; Brilot, Fabienne; Hansenne, Isabelle et al

in Drug Design Reviews - Online (2004), 1

Slightly after the emergence some 400 millions years ago of the first signs of adaptive immune response, tolerogenic pathways developed in order to preserve the integrity of self from potential autoimmune ... [more ▼]

Slightly after the emergence some 400 millions years ago of the first signs of adaptive immune response, tolerogenic pathways developed in order to preserve the integrity of self from potential autoimmune toxicity. Amongst those tolerogenic pathways, the thymus occupies a central place both by deleting self-reactive T cells that are produced in the thymus during random recombination of gene segments encoding the variable parts of the T-cell receptor for antigen (TCR) (negative selection), and by generating self-antigen specific regulatory T cells (Tr). A repertoire of neuroendocrine-related genes are transcribed by thymic stromal cells — epithelial and ‘nurse’ cells (TEC/TNC), dendritic cells (DC) and macrophages (MF) — in such a way that a dominant protein precursor is expressed in the thymus environment. Oxytocin (OT) and neurokinin A (NKA) are the dominant thymic precursors for the neurohypophysial hormone and tachykinin families, respectively. With regard to the insulin gene family, all members are transcribed following a precise cell topography and hierarchy in the profile of gene expression: IGF2 (TEC/TNC) > IGF1 (MF) >> INS (medullary TEC and/or DC). This hierarchy implies that IGF-2 is more tolerated than IGF-1, and much more than Insulin (Ins). The low level of INS transcription in the thymus also explains why Ins displays immunogenic properties, as well as the significant prevalence (±40%) of anti-Ins autoantibodies in the general population. Ins administration failed in providing tolerance or protection toward islet ß cells in type 1 diabetes (T1D). In contrast, the presentation of IGF-2 B11-25, the homologous sequence of Ins B9-23, to peripheral blood mononuclear cells (PBMC) isolated from DQ8+ T1D adolescents significantly increases IL-10 secretion and IL10 expression. Given the potent regulatory/suppressive properties of IL-10 on the autoimmune response toward islet ß cells, these data support that IGF-2 derived sequences constitute a strong basis for the development of an antigen-specific driven tolerogenic approach for T1D prevention and/or cure. [less ▲]

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See detailThe central role of the thymus in the development of self-tolerance and autoimmunity in the neuroendocrine system
Geenen, Vincent ULg; Brilot, Fabienne; Hansenne, Isabelle et al

in Geenen, Vincent; Chrousos, Geroge P. (Eds.) Immunoendocrinology in Health and Disease (2004)

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See detailThymus and T cells
Geenen, Vincent ULg; Brilot, Fabienne; Hansenne, Isabelle et al

in Smith, Barry H.; Adelman, George (Eds.) Encyclopedia of Neuroscience, 3rd Edition (2004)

Evidence for intimate interconnections between the three major systems of cell communication, the nervous, endocrine and immune systems, has opened important novel research perspectives. Neuroimmune ... [more ▼]

Evidence for intimate interconnections between the three major systems of cell communication, the nervous, endocrine and immune systems, has opened important novel research perspectives. Neuroimmune-endocrine interactions are now established as crucial factors for the control of body development and homeostasis. In distant species and invertebrates, the foundations of both the neuroendocrine system and innate immunity were coexisting until now without any apparent problem. Some 400 millions years ago, in a relatively short period after agnathan fishes (e.g., hagfish and lamprey), adaptive immunity emerged in the first gnathostomes, cartilaginous fishes (e.g., shark and ray). Somatic recombination machinery characterizes adaptive immunity and is responsible for the random generation of the huge diversity of immune receptors able to recognize infectious antigens. The emergence of this novel form of immune defenses exerted a so potent pressure that structures and mechanisms developed along the paths of lymphocyte traffic to impose immunological self-tolerance, that is, the inability of the immune system to attack the host organism. Together with the generation of diversity and memory, self-tolerance constitutes a fundamental property of the immune system. The progressive rise in the level of immune diversity and complexity also explains why self-tolerance failures (i.e., organ-specific autoimmune diseases) were increasingly detected during evolution, the maximum being currently observed in the human species. The first thymus appeared in cartilaginous fishes (chondrichthyes), concomitantly with the emergence of rudimental forms of adaptive immunity. Though some forms of tolerance induction already takes place in primary hemopoietic sites (fetal liver and bone marrow), antigen-dependent B-cell tolerance is primarily due to an absence of T-cell help. Among all lymphoid structures, the thymus is the only organ specialized in the establishment of central self-tolerance. The thymus crucially stands at the crossroad between the immune and neuroendocrine systems. In this organ responsible for thymopoiesis—T-cell generation—(Kong et al., 1998), the neuroendocrine system regulates the process of T-cell differentiation from the very early stages. In addition, T lymphocytes undergo inside the thymus a complex educative process that establishes central T-cell self-tolerance of neuroendocrine principles (Geenen et al., 1992; Martens et al., 1996). Within the thymus, a confrontation permanently occurs between previously established neuroendocrine principles and a recent system equipped with recombination machinery promoting stochastic generation of response diversity. Contrary to a previous assumption, the thymus functions throughout life (Poulin et al., 1999; Geenen et al., 2003) and plays a fundamental role in the recovery of a competent T-cell repertoire after intensive chemotherapy or during highly active antiretroviral therapy (Mackall et al., 1995; Douek et al., 1998). [less ▲]

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See detailQuantification of T cell receptor rearrangement excision circles to estimate thymic function: an important new tool for endocrine-immune physiology
Geenen, Vincent ULg; Poulin, J. F.; Dion, M. L. et al

in Journal of Endocrinology (2003), 176(3), 305-311

Although the thymus constitutes a target organ for most protein and steroid hormones, it has been quite difficult to determine the precise control exerted in vivo by the endocrine system upon thymic ... [more ▼]

Although the thymus constitutes a target organ for most protein and steroid hormones, it has been quite difficult to determine the precise control exerted in vivo by the endocrine system upon thymic function. The biological role of the thymus is to ensure the generation of a diversified population of peripheral T cells able to respond to non-self-antigens but nevertheless tolerant to self-antigens. For a long time, thymic function could not be monitored, as a consequence of the absence of adequate technology to differentiate recent thymic emigrants from naive T cells. The generation of T cell receptor (TCR) diversity occurs in the thymus through recombination of gene segments encoding the variable parts of the TCR alpha and beta chains. During these processes, by-products of the rearrangements are generated in the form of TCR excision circles (TRECs). As these molecules are lost upon further cell division, their quantification is actually considered as a very valuable tool to estimate thymic function. The most appropriate TREC is deltaRec-Psi(J)alpha TREC or signal joint TREC resulting from deltaRec-Psi(J)alpha rearrangement (TCRD deletion) that occurs late during thymopoiesis, before V(alpha)-J(alpha) rearrangement. Here we describe how TREC quantification is a powerful and reliable method to evaluate the impact of hormones and endocrine disorders upon thymic function [less ▲]

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See detailThymic IGF-2 and central self-tolerance of the insulin family: a basis for the development of a negative vaccine against type 1 diabetes
Geenen, Vincent ULg; Brilot, Fabienne; Hansenne, Isabelle et al

in Diabetologia (2003), 46 (Suppl. 2)

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See detailOxytocin synthesis and oxytocin receptor expression by cell lines of human small cell carcinoma of the lung stimulate tumor growth through autocrine/paracrine signaling
Pequeux, Christel ULg; Breton, Christophe; Hendrick, Jean-Claude et al

in Cancer Research (2002), 62(16), 4623-4629

The objective of the present work was to investigate the existence of an oxytocin (OT)-mediated autocrine/paracrine signaling upon small cell carcinoma of the lung (SCCL) cell growth. In that view, OT ... [more ▼]

The objective of the present work was to investigate the existence of an oxytocin (OT)-mediated autocrine/paracrine signaling upon small cell carcinoma of the lung (SCCL) cell growth. In that view, OT receptor (OTR) expression, concomitant with OT synthesis and secretion, was evidenced on three different SCCL cell lines (DMS79, H146, and H345) and related to the vasopressin (VP) system. Specific OT, VP, OTR, Via VP receptor (V1aR), and V1b/V3 VP receptor (V1bR/V3R) transcripts were identified by reverse transcription-.PCR in all cell lines studied. Binding of I-125-(d(CH2)(5)(1),Tyr(Me)(2), Thr(4), Orn(3),Tyr(9)-NH2)-vasotocin (OVTA) was observed on all SCCL cell lines, with a K-d (dissociation constant) ranging from 0.025-0.089 nm, depending; on the cell line and the analytical method. Selectivity of I-125-OVTA binding was confirmed by displacement curves obtained with various OTR and VP receptor agonists and antagonists (OT, OVTA, L-371,257, VP, F180). Immunocytochemistry identified cellular OT and VP, and peptide secretion was measured in supernatants of SCCL cultures. [H-3]Thymidine incorporations, applied on H345 cells, demonstrated a dose-dependent mitogenic effect of exogenous OT (1 and 100 nM) that was abolished by the OTR antagonist OVTA. A decrease of proliferation was also observed with OVTA alone, showing a functional mitogenic effect of tumor-derived OT. Taken together, these observations demonstrate the existence of a functional OT-mediated autocrine/paracrine signaling actively implicated in growth and development of SCCL tumors. Furthermore, these findings point to the potential of OT antagonists for development as therapeutic agents for the treatment of SCCL. [less ▲]

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See detailThymic T-cell tolerance of neuroendocrine functions: physiology and pathophysiology
Geenen, Vincent ULg; Kecha, Ouafae; Brilot, Fabienne et al

in Halbhuber, Karl-Jürgen; Kinoshita, Yoshihiro (Eds.) Recent Advances in the Immunobiology of the Thymus (2001)

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See detailCentral self-tolerance by thymic presentation of self-antigens and autoimmunity
Geenen, Vincent ULg; Martens, Henri ULg; Hansenne, Isabelle et al

in Current Medicinal Chemistry - Immunology, Endocrine & Metabolic Agents (2001), 1

Before reacting against non-self infectious agents, the immune system is educated to tolerate the host molecular structure (self). The induction of self-tolerance is a multistep process that begins in the ... [more ▼]

Before reacting against non-self infectious agents, the immune system is educated to tolerate the host molecular structure (self). The induction of self-tolerance is a multistep process that begins in the thymus during fetal ontogeny (central tolerance) and also involves inactivating mechanisms outside the thymus (peripheral tolerance). The thymus is the primary lymphoid organ implicated in the development of competent and self-tolerant T cells. During ontogeny, T cell progenitors originating from hemopoietic tissues (yolk sac, fetal liver, and then bone marrow) enter the thymus and undergo a program of proliferation, T cell receptor (TCR) gene rearrangement, maturation and selection. Close interactions between thymocytes (pre-T cells) and the thymic cellular environment are crucial both for T cell development and induction of central self-tolerance. Thymic epithelial and stromal cells synthesize polypeptides belonging to various neuroendocrine families. The thymic repertoire of neuroendocrine-related precursors transposes at the molecular level the dual role of the thymus in T cell negative and positive selection. Thymic precursors not only constitute a source of growth peptides for cryptocrine signaling between thymic stromal cells and pre-T cells, but are also processed in a way that leads to the presentation of self-antigens by thymic major histocompatibility complex (MHC) proteins. Thymic neuroendocrine self-antigens often correspond to peptide sequences highly conserved during the evolution of their corresponding family. The thymic presentation of some neuroendocrine self-antigens is not restricted by MHC alleles. Following the presentation of neuroendocrine self-antigens by thymic MHC proteins, the T cell system might be educated to tolerate main hormone families. Recent experiments argue that a defect in the thymic essential tolerogenic function is implicated as an important factor in the pathophysiology of many autoimmune diseases. [less ▲]

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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 detailThymic neurohypophysial peptide-mediated signaling and T-cell differentiation
Geenen, Vincent ULg; Martens, Henri ULg; Hansenne, Isabelle

in FASEB Journal (2001), 15

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