BackgroundDespite 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 FindingsTwenty-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/β 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/β 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/β TREC ratio also increased with GH resumption, but did not return to the level measured before GH withdrawal.ConclusionsIn 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 RegistrationClinicalTrials.gov NTC00601419
Aims: We address the question of the expression and the role of the growth hormone/insulin-like growth factor (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. The effect of GH on T cell differentiation was explored via 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 concentrations 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 the GH receptor (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.
Before being able to react against infectious nonself-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 programing central self-tolerance to pancreatic insulin-secreting islet b cells, leading to the breakdown of immune homeostasis with an enrichment of islet b-cell reactive effector T cells and a deficiency of b-cell specific natural regulatory T cells (nTregs) in the peripheral Tlymphocyte 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 demonstrated in many studies, including the failure of all clinical trials that have attempted immune tolerance to islet b cells via various methods of insulin administration. On the basis of the close homology and crosstolerance 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 selfvaccination', is currently being developed for the prevention and cure of T1D. If this approach were found to be effective for reprograming immunological tolerance in T1D, it could pave the way for the design of other self-vaccines against autoimmune endocrine diseases, as well as other organspecific autoimmune diseases. ''Autoimmune disease can be a depressing subject. In Shakespearian terms, 'it is a tale told by an idiot. . .signifying nothing'. In more modern metaphor, it is an error made at random in an enormous, delicately programmed computer. Nature has no other way of handling genetic error than by eliminating the faulty, and the physician handling autoimmune diseases can expect no help from her.'' Sir F. MacFarlane Burnet, 1972 IntroductionIn 1965, our late Belgian colleague Willy Gepts observed inflammatory infiltrates of mononuclear cells invading Langerhans' islets in the pancreas of deceased young diabetic patients [1]. In a prophetical analysis, he discussed his innovative results with the following words: 'It seems probable that, in the pancreas of acute diabetics, we had the opportunity to catch the final stages of a process which has been going on for an indefinite time, perhaps from birth on'. Since this pioneering work, research conducted worldwide has firmly established that type 1 diabetes (T1D) -previously called juvenile diabetes, and insulin-dependent diabetes -is the final result of a highly selective autoimmune response that generates an inflammation (insulitis), followed by the death of insulin-secreting islet b cells in the pancreas. Incidence of T1D peaks around 10-14 years and this disease affects AE20 million people worldwide (approximately 10%...
During a 2-year chronic inhalation study on methylene chloride (2000 or 0 ppm; 6 hr/day, 5 days/week), gas-uptake pharmacokinetic studies and tissue partition coefficient determinations were conducted on female B6C3F1, mice after 1 day, 1 month, 1 year, and 2 years of exposure. Using physiologically based pharmacokinetic (PBPK) modeling coupled with Monte Carlo simulation and bootstrap resampling for data analyses, a significant induction in the mixed function oxidase (MFO) rate constant (Vmaxc) was observed at the 1-day and 1-month exposure points when compared to concurrent control mice while decreases in glutathione S-transferase (GST) rate constant (Kfc) were observed in the 1-day and 1-month exposed mice. Within exposure groups, the apparent Vmaxc maintained significant increases in the 1-month and 2-year control groups. Although the same initial increase exists in the exposed group, the 2-year Vmaxc is significantly smaller than the 1-month group (p < 0.001). Within group differences in median Kfc values show a significant decrease in both 1-month and 2-year groups among control and exposed mice (p < 0.001). Although no changes in methylene chloride solubility as a result of prior exposure were observed in blood, muscle, liver, or lung, a marginal decrease in the fat:air partition coefficient was found in the exposed mice at p = 0.053. Age related solubility differences were found in muscle:air, liver:air, lung:air, and fat:air partition coefficients at p < 0.001, while the solubility of methylene chloride in blood was not affected by age (p = 0.461). As a result of this study, we conclude that age and prior exposure to methylene chloride can produce notable changes in disposition and metabolism and may represent important factors in the interpretation for toxicologic data and its application to risk assessment.ImagesFigure 1.Figure 2.Figure 3.Figure 4.Figure 4.Figure 4.Figure 4.Figure 5.Figure 5.Figure 5.Figure 5.
Abstract: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 novel therapeutic agents that could be used for enhancing thymopoiesis in different cases of immune deficiencies, including aging-related immune dysfunction.Keywords: Thymus, growth hormone (GH), insulin-like growth factors (IGFs), HIV, growth hormone deficiency (GHD), Chagas disease. GENERAL INTRODUCTIONThe thymus is now considered as a crucial organ for maintenance of immune system homeostasis and the central lymphoid organ where occurs the generation of self-tolerant and competent naive T cells, as well as self-antigen specific natural Treg cells [1,2]. However, for a long time, the thymus has been regarded as an endocrine gland. In addition, the thymus now appears as a privileged site where the endocrine and immune systems intimately interact.A permanent crosstalk exists between the neuroendocrine and immune systems [3][4][5][6]. In addition to the strong modulation of immunity by glucocorticoids and sexual steroids, other hormones have been more and more involved in immunomodulation. Indeed, the somatotrope GH/IGF-1 axis, as well as prolactin and thyroid hormones [7], were shown to play an important regulatory role in T-cell development [8][9][10].GH is mainly synthesised in the anterior pituitary gland but can also be produced by immune cells [11,12]. GH has several biological actions in the immune system including regulation of thymopoiesis and T-cell development [13]. Nevertheless, it is uneasy to distinguish whether the thymotropic effects of GH are direct or mediated by IGF-1, as most *Address correspondence to this author at the University of Liege Center of Immunoendocrinology (CIL), Institute of Pathology CHU-B23, B-4000 Liege-Sart Tilman, Belgium; Tel: +32 43 66 25 50; Fax: +32 43 66 98 59; E-mail: vgeenen@ulg.ac.be of GH effects are driven by induction of IGF-1 and as IGF-1 has also been described as an endogenous factor in the thymic microenvironment [12]. The evolution of the research field has brought new insights that justify an overview update as some ancie...
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