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See detailA surprising and dramatic neuroendocrine-immune phenotype of mice deficient in Growth Hormone-Releasing Hormone (GHRH)
Farhat, Khalil; Bodart, Gwennaëlle ULg; RENARD, Jeanne de Chantal ULg et al

Poster (2017, May 23)

In the framework of close interactions between the immune and neuroendocrine systems, Growth Hormone (GH) has been proposed to exert significant effects on the immune system, but there is not yet a ... [more ▼]

In the framework of close interactions between the immune and neuroendocrine systems, Growth Hormone (GH) has been proposed to exert significant effects on the immune system, but there is not yet a consensus about GH immunomodulatory properties. These studies investigated the immune and anti-infectious response of dwarf Ghrh-/- mice presenting a severe deficiency of the GHRH/GH/IGF-1 axis. In basal conditions, thymic parameters and T-cell responses of Ghrh-/- mice were not severely affected but a constant B-cell lymphopaenia was observed. Thus, we investigated vaccine and anti-infectious responses of Ghrh-/- mice toward Streptococcus pneumonia, a B-dependent pathogen, 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. These vaccines both include the serotype 1 (our S.pneumoniae strain) and provide an effective protection in mice. 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 could exert distinct impacts upon spenic areas. Furthermore, after intranasal instillation of a non-lethal dose (defined by the full clearance by WT C57BL/6 mice after 24h) of serotype 1 S.pneumoniae, Ghrh-/- mice exhibited a dramatic susceptibility. This was proved by a marked time-dependent increase in pulmonary bacterial, a septicemia already 24h after infection and a survival limit of 72h. We also observed a dramatic decrease in lung B- and T-cell populations and an increase in proportion of inflammatory macrophages. By contrast, wild-type and heterozygote mice completely cleared S.pneumoniae infection after 24h. In conclusion, our data show without ambiguity that the somatotrope GHRH/GH/IGF-1 axis plays an important and unsuspected role in defense against S.Pneumoniae. [less ▲]

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See detailMechanisms of Igf2 inhibition in thymic epithelial cells infected with CVB4 E2
Michaux, Hélène ULg; Charlet-Renard, Chantal; Martens, Henri ULg et al

Poster (2017, March 12)

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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 detailA surprising and dramatic neuroendocrine-immune phenotype of mice deficient in Growth Hormone-Releasing Hormone (GHRH)
Farhat, Khalil; Bodart, Gwennaelle; Martens, Henri ULg et al

in Neuroimmunomodulation (2017)

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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 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 detailMechanisms of Igf2 inhibition in thymic epithelial cells infected with CV-B4 E2
Michaux, Hélène ULg; Charlet-Renard, Chantal; Martens, Henri ULg et al

Poster (2016, May 03)

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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)

Detailed reference viewed: 56 (15 ULg)