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See detailThe use of oxytocin to improve feeding and social skills in infants with Prader-Willi syndrome
Tauber, Maïthé; Boulanouar, Kader; Gwenaelle, Diene et al

in Pediatrics (2017), 139(2),

BACKGROUND AND OBJECTIVES: Patients with Prader–Willi syndrome (PWS) display poor feeding and social skills as infants and fewer hypothalamic oxytocin (OXT)-producing neurons were documented in adults ... [more ▼]

BACKGROUND AND OBJECTIVES: Patients with Prader–Willi syndrome (PWS) display poor feeding and social skills as infants and fewer hypothalamic oxytocin (OXT)-producing neurons were documented in adults. Animal data demonstrated that early treatment with OXT restores sucking after birth. Our aim is to reproduce these data in infants with PWS. METHODS: We conducted a phase 2 escalating dose study of a short course (7 days) of intranasal OXT administration. We enrolled 18 infants with PWS under 6 months old (6 infants in each step) who received 4 IU of OXT either every other day, daily, or twice daily. We investigated the tolerance and the effects on feeding and social skills and changes in circulating ghrelin and brain connectivity by functional MRI. RESULTS: No adverse events were reported. No dose effect was observed. Sucking assessed by the Neonatal Oral-Motor Scale was abnormal in all infants at baseline and normalized in 88% after treatment. The scores of Neonatal Oral-Motor Scale and videofluoroscopy of swallowing significantly decreased from 16 to 9 (P < .001) and from 18 to 12.5 (P < .001), respectively. Significant improvements in Clinical Global Impression scale scores, social withdrawal behavior, and mother–infant interactions were observed. We documented a significant increase in acylated ghrelin and connectivity of the right superior orbitofrontal network that correlated with changes in sucking and behavior. CONCLUSIONS: OXT is well tolerated in infants with PWS and improves feeding and social skills. These results open perspectives for early treatment in neurodevelopment diseases with feeding problems. [less ▲]

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See detailThe somatotrope Growth Hormone-Releasing Hormone/Growth Hormone/Insulin-like Growth Factor 1 axis in immunoregulation and immunosenescence
Bodart, Gwennaëlle ULg; Farhat, Khalil; RENARD, Jeanne de Chantal ULg et al

in Savino, Wilson; Guaraldi, Federica (Eds.) Endocrine Immunology (2017)

Most scientific reports debate the thymotropic and immuno-stimulating properties of the somato- trope growth hormone-releasing hormone (GHRH)/growth hormone (GH)/insulin-like growth factor (IGF)-1 axis ... [more ▼]

Most scientific reports debate the thymotropic and immuno-stimulating properties of the somato- trope growth hormone-releasing hormone (GHRH)/growth hormone (GH)/insulin-like growth factor (IGF)-1 axis, but there is still some disagreement about the physiological role of this axis in basal conditions. Moreover, some authors have hypothesized that the physiological role of the somato- trope axis only appears in stressful conditions (such as sepsis or infective and inflammatory diseases). This chapter will provide an extended overview of the expression of the components (signals and receptors) of the somatotrope axis and their properties on cells of the innate and adaptive immune system. It will also summarize some clinical studies suggesting a benefit for a short-term GH treat- ment in acute immunodeficiencies, and the importance of GH supplementation in adult GH defi- ciency. A new transgenic mouse model, the hypothalamic GHRH-deficient (Ghrh–/–) mouse, which exhibits a severe deficiency of the somatotrope axis, will be presented since it will be of great help in further deciphering the regulation by the GHRH/GH/IGF-1 axis on both immune development and function. Finally, we will discuss the implication of aging-related somatopause in relation to the general context of Immunosenescence. [less ▲]

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See detailSevere deficiency of the somatotrope GHRH/GH/IGF-1 axis induces a dramatic susceptibility to Streptococcus pneumoniae infection.
Farhat, Khalil ULg; Bodart, Gwennaëlle ULg; Desmet, Christophe ULg et al

Poster (2016, November 07)

Deletion of the growth hormone-releasing hormone gene (Ghrh) results in a severe deficiency of the somatotrope GHRH-GH-IGF-1 axis causing dwarf phenotype that can be reversed by GH or GHRH supplementation ... [more ▼]

Deletion of the growth hormone-releasing hormone gene (Ghrh) results in a severe deficiency of the somatotrope GHRH-GH-IGF-1 axis causing dwarf phenotype that can be reversed by GH or GHRH supplementation (Alba & Salvatori, Endocrinology 2004;145:4134). In basal conditions, the immunological phenotype of Ghrh-/- mice is not markedly disturbed except for a decrease in B cells and an increase in generation of thymic (t) Treg cells (submitted for publication). These data prompted us to investigate immune responses of Ghrh-/- mice using vaccination and infection by S. pneumoniae as models since the response to both stimuli rely on the innate immune system and B cells. Ghrh-/- mice were unable to trigger production of specific IgM and IgG against serotype 1 pneumococcal polysaccharide (PPS) after vaccination with either native PPS (Pnx23) or protein-PPS conjugate (Prev-13) vaccines. A short GH supplementation to Ghrh-/- mice (1 daily injection of 1 mg/kg GH for 4 weeks) restored IgM and IgG response to Pnx23 vaccine but not to Prev-13. This suggests that GH differently impacts on B-1, marginal zone B-2 or innate B-1 B cells. Furthermore, after intranasal instillation of a non-lethal dose of serotype 1 S. pneumoniae, Ghrh-/- mice exhibited a dramatic susceptibility reflected by bacteremia 24h after infection and a survival limit of 72 h, compared to WT C57BL/6 mice that need only 24h to clear infection. The possible impact of GH deficiency on components of the innate immune system that play an important role in defense of the respiratory tract against pneumococcal infection is under current investigation. (*Equal first and last authors. KF is supported by a research grant from the Lebanese Government; GB is Research Assistant, CD is Research Associate, and VG is Research Director at the NFSR of Belgium). [less ▲]

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See detailTreg, Th17 and γδ T cells during normal and abortive pregnancy
Polese, Barbara ULg; Gridelet, Virginie ULg; Munaut, Carine ULg et al

Poster (2016, October 14)

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See detailTreg, Th17 and γδ T cells during normal and abortive pregnancy
Polese, Barbara ULg; Gridelet, Virginie ULg; Munaut, Carine ULg et al

Conference (2016, October 14)

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See detailOxytocin in survivors of childhood-onset craniopharyngioma
Daubenbüchel, Anna; Hoffmann, Anika; Eveslage, Maria et al

in Endocrine (2016)

Quality of survival of childhood-onset cranio- pharyngioma patients is frequently impaired by hypotha- lamic involvement or surgical lesions sequelae such as obesity and neuropsychological deficits ... [more ▼]

Quality of survival of childhood-onset cranio- pharyngioma patients is frequently impaired by hypotha- lamic involvement or surgical lesions sequelae such as obesity and neuropsychological deficits. Oxytocin, a pep- tide hormone produced in the hypothalamus and secreted by posterior pituitary gland, plays a major role in regula- tion of behavior and body composition. In a cross- sectional study, oxytocin saliva concentrations were ana- lyzed in 34 long-term craniopharyngioma survivors with and without hypothalamic involvement or treatment- related damage, recruited in the German Childhood Cra- niopharyngioma Registry, and in 73 healthy controls, attending the Craniopharyngioma Support Group Meeting 2014. Oxytocin was measured in saliva of craniophar- yngioma patients and controls before and after standar- dized breakfast and associations with gender, body mass index, hypothalamic involvement, diabetes insipidus, and irradiation were analyzed. Patients with preoperative hypothalamic involvement showed similar oxytocin levels compared to patients without hypothalamic involvement and controls. However, patients with surgical hypotha- lamic lesions grade 1 (anterior hypothalamic area) pre- sented with lower levels (p = 0.017) of oxytocin under fasting condition compared to patients with surgical lesion of posterior hypothalamic areas (grade 2) and patients without hypothalamic lesions (grade 0). Craniophar- yngioma patients’ changes in oxytocin levels before and after breakfast correlated (p = 0.02) with their body mass index. Craniopharyngioma patients continue to secrete oxytocin, especially when anterior hypothalamic areas are not involved or damaged, but oxytocin shows less varia- tion due to nutrition. Oxytocin supplementation should be explored as a therapeutic option in craniopharyngioma patients with hypothalamic obesity and/or behavioral pathologies due to lesions of specific anterior hypotha- lamic areas. Clinical trial number: KRANIOPHAR- YNGEOM 2000/2007(NCT00258453; NCT01272622). [less ▲]

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See detailTreg, Th17 and γδ T cells during normal and abortive pregnancy
Polese, Barbara ULg; Gridelet, Virginie ULg; Munaut, Carine ULg et al

Poster (2016, January 25)

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See detailSomatotrope GHRH/GH/IGF-1 axis at the crossroad between immunosenescence and elder frailty
Bodart, Gwennaëlle ULg; Goffinet, Lindsay; Morrhaye, Gabriel et al

in Annals of the New York Academy of Sciences (2015), 1351

Immunosenescence as complex modifications of immunity with age could be related to the so-called frailty syndrome of elderly leading to an inadequate response to minimal aggression. Functional decline ... [more ▼]

Immunosenescence as complex modifications of immunity with age could be related to the so-called frailty syndrome of elderly leading to an inadequate response to minimal aggression. Functional decline, the loss of ability to perform activities of daily living, is related to the decrease in physiological reserves and frailty and is a frequent outcome of hospitalization in older patients. Links between immunosenescence and frailty were explored and 20 immunological parameters were affected in seniors with functional decline. IGF-1, thymopoeisis and telomere length were part of these markers. A strong relationship between insulin-like growth factor-1 (IGF-1) and thymic ouput was evidenced. IGF-1, mediator of GH, was subsequently shown to induce IL-7 secretion in cultured primary human thymic epithelial cells (TECs). We are also exploring the ‘stress hypothesis’ according which an acute stress is the discriminator revealing a frailty susceptility. GH can counteract the deleterious immunosuppressive effect of stress-induced steroids. Under non-stressing conditions, the immunosenescent system preserves physiological responses, while in stressing conditions, the combination of immunosenescence and a defect in somatotrope axis might lead to functional decline. [less ▲]

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See detailHow does thymus infection by coxsackievirus contribute to the pathogenesis of type 1 diabetes?
Michaux, Hélène ULg; Martens, Henri ULg; Jaïdane, Hela et al

in Frontiers in Immunology (2015), 6(Article 338), 1-6

Through synthesis and presentation of neuroendocrine self-antigens by major histocom- patibility complex proteins, thymic epithelial cells (TECs) play a crucial role in programing central immune self ... [more ▼]

Through synthesis and presentation of neuroendocrine self-antigens by major histocom- patibility complex proteins, thymic epithelial cells (TECs) play a crucial role in programing central immune self-tolerance to neuroendocrine functions. Insulin-like growth factor- 2 (IGF-2) is the dominant gene/polypeptide of the insulin family that is expressed in TECs from different animal species and humans. Igf2 transcription is defective in the thymus of diabetes-prone bio-breeding rats, and tolerance to insulin is severely decreased in Igf2−/− mice. For more than 15 years now, our group is investigating the hypothesis that, besides a pancreotropic action, infection by coxsackievirus B4 (CV- B4) could implicate the thymus as well, and interfere with the intrathymic programing of central tolerance to the insulin family and secondarily to insulin-secreting islet β cells. In this perspective, we have demonstrated that a productive infection of the thymus occurs after oral CV-B4 inoculation of mice. Moreover, our most recent data have demonstrated that CV-B4 infection of a murine medullary (m) TEC line induces a significant decrease in Igf2 expression and IGF-2 production. In these conditions, Igf1 expression was much less affected by CV-B4 infection, while Ins2 transcription was not detected in this cell line. Through the inhibition of Igf2 expression in TECs, CV-B4 infection could lead to a breakdown of central immune tolerance to the insulin family and promote an autoimmune response against insulin-secreting islet β cells. Our major research objective now is to understand the molecular mechanisms by which CV-B4 infection of TECs leads to a major decrease in Igf2 expression in these cells. [less ▲]

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See detailTreg/Th17 balance during murine embryo implantation and pregnancy
Polese, Barbara ULg; Gridelet, Virginie ULg; Araklioti, Eleni et al

Poster (2014, November)

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See detailThe endocrine milieu and CD4 T-lymphocyte polarization during pregnancy
Polese, Barbara ULg; Gridelet, Virginie ULg; Arakioti, Eleni et al

in Frontiers in Endocrinology (2014), 5(Article 106), 1-11

Acceptance of the fetal semi-allograft by the mother’s immune system has become the focus of intensive research. CD4+ T cells are important actors in the establishment of pregnancy. Th1/Th2 paradigm has ... [more ▼]

Acceptance of the fetal semi-allograft by the mother’s immune system has become the focus of intensive research. CD4+ T cells are important actors in the establishment of pregnancy. Th1/Th2 paradigm has been expanded to include CD4+ regulatory T (Treg) and T helper 17 (Th17) cells. Pregnancy hormones exert very significant modulatory properties on the maternal immune system. In this review, we describe mechanisms by which the endocrine milieu modulates CD4 T cell polarization during pregnancy. We first focused on Treg and Th17 cells and on their importance for pregnancy. Secondly, we review the effects of pregnancy hormones [progesterone (P4) and estradiol (E2)] on immune cells previously described, with a particular attention to human chorionic gonadotropin (hCG). The importance of Treg cells for pregnancy is evidenced. They are recruited before implantation and are essential for pregnancy maintenance. Decreased number or less efficient Treg cells are implicated in fertility disorders. As for Th17 cells, the few available studies suggest that they have a negative impact on fertility. Th17 frequency is increased in infertile patients. With the combination of its pro-effects on Th2 and Treg cells and anti-effects on Th1 and Th17 cells, P4 contributes to establishment of a favorable environment for pregnancy. E2 effects are more dependent on the context but it seems that E2 promotes Treg and Th2 cells while it inhibits Th1 cells. hCG positively influences activities of Treg and uterine natural killer cells. This embryo signal is an essential actor for the success of pregnancy, both as the endocrine factor regulating P4 secretion by the ovarian corpus luteum, but also as a paracrine agent during implantation as well as an angiogenic and immunologic mediator during the course of gestation. Luteinizing hormone (LH) immune properties begin to be studied but its positive impact on Treg cells suggests that LH could be a considerable immunomodulator in the mouse. [less ▲]

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See detailPréservation de la thymopïèse dans le grand âge
RICOUR, Céline ULg; de saint hubert, Marie; Martens, Henri ULg et al

Poster (2014)

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See detailProgramming of neuroendocrine self in the thymus and its defect in neuroendocrine autoimmunity
Geenen, Vincent ULg; Bodart, Gwennaëlle ULg; Henry, Séverine et al

in Frontiers in Neuroscience (2013), 7

During centuries after its first description by Galen, the thymus has been considered only as a vestigial endocrine organ until the discovery in 1961 by Jacques FAP Miller of its essential role in the ... [more ▼]

During centuries after its first description by Galen, the thymus has been considered only as a vestigial endocrine organ until the discovery in 1961 by Jacques FAP Miller of its essential role in the development of T (thymo-dependent) lymphocytes. A unique thymus appeared for the first time in cartilaginous fishes some 500 millions years ago, in the same time or shortly after the emergence of the adaptive (acquired) immune system. The thymus may be compared to a small brain or a computer highly specialized in the orchestration of central immunological self-tolerance. This latter was a necessity for the survival of species given the potent evolutionary pressure impacted by the high risk of autotoxicity inherent to the stochastic generation of the diversity of immune cell receptors that characterize the adaptive immune response. The new paradigm of neuroendocrine self-peptides has been proposed together with the definition of neuroendocrine self. Neuroendocrine self-peptides are not secreted by thymic epithelial cells (TECs) according to the classic model of neuroendocrine signaling, but processed for a presentation by, or in association with, the thymic major histocompatibility complex (MHC) proteins. The autoimmune regulator (AIRE) gene/protein controls the transcription of neuroendocrine genes in TECs. The presentation of self-peptides in the thymus is responsible for the clonal deletion of self-reactive T cells emerging during the random recombination of gene segments that encode variable parts of the T cell receptor for the antigen (TCR). In the same time, self-antigen presentation in the thymus also generates regulatory T (Treg) cells that are able to inhibit in the periphery self-reactive T cells having escaped negative selection in the thymus. Several arguments show that the origin of autoimmunity directed against neuroendocrine glands primarily results from a defect in the intrathymic programming of self-tolerance to neuroendocrine functions. This defect may be genetic or acquired during an enteroviral infection, for example. This novel knowledge of normal and pathologic functions of the thymus already constitutes a solid basis for the development of a novel type of tolerogenic/negative self-vaccination against type 1 diabetes (T1D). [less ▲]

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