Impact of Growth Hormone (GH) Deficiency and GH Replacement upon Thymus Function in Adult Patients

Abstract

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

Thymic self-antigens for the design of a negative/tolerogenic self-vaccination against type 1 diabetes

“…Contrary to popular opinion, the thymus continues to function throughout life and plays a fundamental role in the recovery of a competent T-cell repertoire after intensive chemotherapy or during highly active antiretroviral chemotherapy in human immunodeficiency virus infection [60,61]. The integrity of the somatotrope growth hormone/IGF-1 axis is known to be important for the maintenance of thymus function in adult life [62 ].…”

“…Contrary to popular opinion, the thymus continues to function throughout life and plays a fundamental role in the recovery of a competent T-cell repertoire after intensive chemotherapy or during highly active antiretroviral chemotherapy in human immunodeficiency virus infection [60,61]. The integrity of the somatotrope growth hormone/IGF-1 axis is known to be important for the maintenance of thymus function in adult life [62 ].The thymus constitutes the central arm of immunological self-tolerance by two essential mechanisms that are intimately associated with, and paradoxically mediated by, the same thymic self-antigens: first, clonal deletion of self-reactive T cells issued from the random recombination of TCR genes (negative selection) and second, generation of self-antigen-specific natural regulatory T cells (nTregs) that are able to inactivate in periphery selfreactive T cells having escaped intrathymic negative selection [63 ,64].For a long time, peripheral tissue-restricted antigens targeted by autoimmune processes were thought to be sequestered from T cells during their intrathymic differentiation. We and several other groups have demonstrated that thymic epithelial cells (TECs) from different species constitute a site for the promiscuous transcription of a great number of genes encoding tissuerestricted antigens or belonging to neuroendocrine families, such as the neurohypophysial family, tachykinins, neurotensins, somatostatins, atrial natriuretic peptides, and the insulin family.…”

Impact of the Somatotrope Growth Hormone (GH)/Insulin-Like Growth Factor 1 (IGF-1) Axis Upon Thymus Function: Pharmacological Implications in Regeneration of Immune Functions

“…Furthermore, these increases of TREC frequency and T-cell gain are correlated to an increase of plasma IGF-1 [15], arguing for a crucial role of IGF-1 in GH-mediated stimulation of thymic T-cell production. Investigation of thymopoiesis in adult GH deficiency (AGHD) has demonstrated that, after GH withdrawal, intrathymic T-cell proliferation and thymic T-cell output decreased whereas resumption of GH treatment led to an increase of thymopoiesis to a level close to the one before withdrawal of GH treatment [16]. Again, in this study, the close correlation between plasma IGF-1 concentrations and the frequency of sjTREC in PBMC suggests that the thymotropic properties of GH could be mediated by IGF-1 [16].…”

“…Investigation of thymopoiesis in adult GH deficiency (AGHD) has demonstrated that, after GH withdrawal, intrathymic T-cell proliferation and thymic T-cell output decreased whereas resumption of GH treatment led to an increase of thymopoiesis to a level close to the one before withdrawal of GH treatment [16]. Again, in this study, the close correlation between plasma IGF-1 concentrations and the frequency of sjTREC in PBMC suggests that the thymotropic properties of GH could be mediated by IGF-1 [16]. It should be also noted that the effects of the somatotrope GH/IGF-1 axis on thymocytes might be relayed by other soluble factors like cytokines.…”

“…The evolution of the research field has brought new insights that justify an overview update as some ancient conclusions about absence of GH receptor on human differentiating T cells, or the lack of effect of GH administration on human thymopoiesis, have been recently revisited. Finally, from the data of recent studies, it has been proposed that GH and IGF-1 could be novel therapeutic agents able to enhance thymopoiesis in immunodeficient individuals [14][15][16]. …”