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See detailExpression of growth hormone (GH)/insulin-like growth factor (IGF) axis during Balb/c ontogeny and effects of GH upon ex-vivo T-cell differentiation
Kermani, Hamid; Goffinet, Lindsay ULg; Mottet, Marie ULg et al

in Neuroimmunomodulation (2012), 19

Aims: We here address the question of expression and role of GH/IGF axis in the thymus. Methods: Using RT-qPCR, the expression profile of various components of the somatotrope GH/IGF axis was measured in ... [more ▼]

Aims: We here address the question of expression and role of GH/IGF axis in the thymus. Methods: Using RT-qPCR, the expression profile of various components of the somatotrope GH/IGF axis was measured in different thymic cell types and during thymus embryogenesis in Balb/c mice. Effect of GH on T-cell differentiation was explored through thymic organotypic culture. Results: Transcription of Gh, Igf1, Igf2 and their related receptors predominantly occurred in thymic epithelial cells (TEC), while a low level of Gh and Igf1r transcription was also evidenced in thymic T cells (thymocytes). Gh, Ghr, Ins2, Igf1, Igf2, and Igfr1, displayed distinct expression profiles depending on the developmental stage. The protein concentration of IGF-1 and IGF-2 were in accordance with the profile of their gene expression. In fetal thymus organ cultures (FTOC) derived from Balb/c mice, treatment with exogenous GH resulted in a significant increase of double negative CD4-CD8- T cells and CD4+ T cells, together with a decrease in double positive CD4+CD8+ T cells. These changes were inhibited by concomitant treatment with GH and GHR antagonist pegvisomant. However, GH treatment also induced a significant decrease in FTOC Gh, Ghr and Igf1 expression. Conclusion: These data show that the thymotropic properties of the somatotrope GH/IGF-1 axis involve an interaction between exogenous GH and GHR expressed by TEC. Since thymic IGF-1 is not increased by GH treatment, the effects of GH upon T-cell differentiation could implicate a different local growth factor or cytokine. [less ▲]

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See detailInvestigations on the mechanisms underlying the thymotropic properties of the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis.
Goffinet, Lindsay ULg; Bodart, Gwennaëlle ULg; Renard, Chantal et al

Poster (2011, November 18)

Background. The thymus is responsible for thymopoiesis, i.e. the generation of a diverse and self-tolerant T-cell repertoire including self-antigen specific natural regulatory cells. We have shown that ... [more ▼]

Background. The thymus is responsible for thymopoiesis, i.e. the generation of a diverse and self-tolerant T-cell repertoire including self-antigen specific natural regulatory cells. We have shown that two parameters of thymopoiesis, thymic output of new T cells (estimated by sjTREC frequency) and intrathymic proliferation of T-cell precursors (estimated by sj/Dβ TREC ratio) are severely reduced in adult patients with GH deficiency (AGHD) and are restored by GH injections at physiological doses. In patients with AGHD, there is a very positive correlation between sjTREC frequency and plasma concentrations of IGF-1, the principal mediator of GH action (1). Treatment of HIV+ patients with high pharmacological doses of GH is associated with increased thymic mass and output of circulating naïve and total CD4+ T cells (2). In addition, previous studies have suggested thymic epithelial cells (TEC) and/or thymocytes (thymic T cells) could transcribe the GH gene (3). Objectives and hypothesis. These studies analysed the question of GH transcription and regulation in primary cultures of human (h) TEC. We also investigated the hypothesis that the thymotropic properties of the somatotrope GH/IGF-1 axis could be mediated by thymic interleukin 7 (IL-7), which plays a crucial role in promoting V(D)J recombination at the TCR locus. Results. Primary hTEC cultures were treated with natural secretagogues of pituitary GH, GH releasing hormone (GHRH) and ghrelin. Using sensitive RT-qPCR, we detected neither any transcript of GH or GHV (placental GH variant) in cultured hTEC, nor any transcript of PIT1, the specific transcription factor of pituitary GH. Similarly, the protein GH was detected neither in the cytoplasm nor in the supernatant of cultured hTEC. Only at 1 nM, GH treatment enhanced IGF1 transcription by cultured hTEC. Of high interest, treatment with GH, ghrelin and IGF-1 promoted IL7 transcription by cultured hTEC, but only IGF-1 and epidermal growth factor (EGF) markedly stimulated IL-7 secretion by hTEC in a dose- and time-dependent manner. The specificity of IGF-1 action was demonstrated by its inhibition after treatment with αIR3, a monoclonal antibody against the type 1 IGF receptor. Conclusions and perspectives. Since primary cultures of hTEC neither transcribe nor secrete any significant amount of GH, the thymotropic effects of the GH/IGF-1 axis seem to depend only on systemic endocrine GH. Local thymic IGF-1 could partially mediate GH action within the thymus and act upon thymopoiesis in parallel with systemic IGF-1. Most importantly, thymic IL-7 appears to be an important mediator of the thymotropic properties of the GH/IGF-1 axis. Further knowledge in this domain will be gained with the use and supplementation of Ghrh-/- mice that will be soon available in our laboratory. References 1. Morrhaye G. et al., PLoS ONE 2009, 4:e5668. 2. Napolitano LA et al. J Clin Invest 2008, 118:1085. 3. Smaniotto S et al., Endocrinology 2005, 146:3005. 4. Taub DD, Murphy WJ and Longo DL. Curr Opin Pharmacol 2010, 10:408. (Supported by F.R.S.-FNRS and a Pfizer Independent Research Grant.) [less ▲]

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See detailInsulin-like growth factor 1 (IGF-1) promotes interleukin 7 (IL-7) synthesis and secretion by primary cultures of human thymic epithelial cells
Goffinet, Lindsay ULg; Renard-Charlet, Chantal; Martens, Henri ULg et al

in Scandinavian Journal of Immunology (2011, April), 73

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See detailThe role of the thymus in integrated evolution of the recombinase-dependent adaptive immune response and the neuroendocrine system
Mottet, Marie ULg; Goffinet, Lindsay ULg; Beckers, Alisson et al

in Neuroimmunomodulation (2011), 18

Before being able to react against infectious non-self antigens, the immune system has to be educated in recognition and tolerance of neuroendocrine self-proteins. This sophisticated educational process ... [more ▼]

Before being able to react against infectious non-self antigens, the immune system has to be educated in recognition and tolerance of neuroendocrine self-proteins. This sophisticated educational process takes place only in the thymus. The development of an autoimmune response directed to neuroendocrine glands has been shown to result from a thymus dysfunction in programming immunological self-tolerance to neuroendocrine-related antigens. This thymus dysfunction leads to a breakdown of immune homeostasis with an enrichment of ‘forbidden’ self-reactive T cells and a deficiency in self-antigen specific natural regulatory T cells (nTreg) in the peripheral T-lymphocyte repertoire. A large number of neuroendocrine self-antigens are expressed by the thymic epithelium, under the control of the autoimmune regulator (AIRE) gene/protein in the medulla. Based on the close homology and cross-tolerance between thymic type 1 diabetes-related self-antigens and peripheral antigens targeted in β cells by autoimmunity, a novel type of vaccination is currently developed for prevention and cure of type 1 diabetes. If this approach were found to be effective in reprogramming immunological tolerance that is absent or broken in this disease, it could pave the way for the design of negative/tolerogenic self-vaccines against other endocrine and organ-specific autoimmune disorders. [less ▲]

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See detailImpact of the somatotrope Growth Hormone (GH)/Insulin-like Growth Factor 1 (IGF-1) axis upon thymus function: Pharmacological implications in regeneration of immune functions
Goffinet, Lindsay ULg; Mottet, Marie ULg; Kermani, Hamid et al

in Immunology, Endocrine & Metabolic Agents - Medicinal Chemistry (2011), 11

The thymus is the central lymphoid structure where T-cell differentiation takes place, and a crucial organ for the maintenance of homeostasis in the immune system. Thymopoiesis includes intrathymic ... [more ▼]

The thymus is the central lymphoid structure where T-cell differentiation takes place, and a crucial organ for the maintenance of homeostasis in the immune system. Thymopoiesis includes intrathymic proliferation of T-cell precursors, selection and output of both self-tolerant and competent effector T cells, as well as of natural regulatory T cells (nTreg). In the crosstalk between the neuroendocrine and immune systems, peptide hormones have been more and more implicated in immunomodulation for the last thirty years. The somatotrope growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis in particular has been repeatedly shown to play a major regulatory role upon thymus function and T-cell development. This review will focus on the important thymotropic properties of the somatotrope GH/IGF-1 axis, and will try to discriminate these properties in function of the endocrine or paracrine/autocrine pathways involved in their mediation. Most importantly, in light of an increasing number of recent studies, GH and IGF-1 now appear as a novel therapeutic agents that could be used for enhancing thymopoiesis in different cases of immune deficiencies, including aging-related immune dysfunction. [less ▲]

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