The Experts below are selected from a list of 1884 Experts worldwide ranked by ideXlab platform
Gregory D Sempowski - One of the best experts on this subject based on the ideXlab platform.
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Acute Endotoxin-Induced Thymic Atrophy Is Characterized By IntraThymic Inflammatory and Wound Healing Responses
2016Co-Authors: Matthew J Billard, Amanda L Gruver, Gregory D SempowskiAbstract:Background: Productive thymopoiesis is essential for a robust and healthy immune system. Thymus unfortunately is acutely sensitive to stress resulting in Involution and decreased T cell production. Thymic Involution is a complication of many clinical settings, including infection, malnutrition, starvation, and irradiation or immunosuppressive therapies. Systemic rises in glucocorticoids and inflammatory cytokines are known to contribute to Thymic atrophy. Little is known, however, about intraThymic mechanisms that may actively contribute to thymus atrophy or initiate Thymic recovery following stress events. Methodology/Principal Findings: Phenotypic, histologic and transcriptome/pathway analysis of murine Thymic tissue during the early stages of endotoxemia-induced Thymic Involution was performed to identify putative mechanisms that drive Thymic Involution during stress. Thymus atrophy in this murine model was confirmed by down-regulation of genes involved in T cell development, cell activation, and cell cycle progression, correlating with observed phenotypic and histologic thymus Involution. Significant gene changes support the hypothesis that multiple key intraThymic pathways are differentially activated during stress-induced Thymic Involution. These included direct activation of thymus tissue by LPS through TLR signaling, local expression of inflammatory cytokines, inhibition of T cell signaling, and induction of wound healing/tissue remodeling. Conclusions/Significance: Taken together, these observations demonstrated that in addition to the classic systemi
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acute endotoxin induced Thymic atrophy is characterized by intraThymic inflammatory and wound healing responses
PLOS ONE, 2011Co-Authors: Matthew J Billard, Amanda L Gruver, Gregory D SempowskiAbstract:Background Productive thymopoiesis is essential for a robust and healthy immune system. Thymus unfortunately is acutely sensitive to stress resulting in Involution and decreased T cell production. Thymic Involution is a complication of many clinical settings, including infection, malnutrition, starvation, and irradiation or immunosuppressive therapies. Systemic rises in glucocorticoids and inflammatory cytokines are known to contribute to Thymic atrophy. Little is known, however, about intraThymic mechanisms that may actively contribute to thymus atrophy or initiate Thymic recovery following stress events.
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leptin receptor is expressed in thymus medulla and leptin protects against Thymic remodeling during endotoxemia induced thymus Involution
Journal of Endocrinology, 2009Co-Authors: Amanda L Gruver, Melissa S Ventevogel, Gregory D SempowskiAbstract:Leptin deficiency in mice results in chronic Thymic atrophy, suppressed cell-mediated immunity, and decreased numbers of total lymphocytes, suggesting a key role for the metabolic hormone leptin in regulating thymopoiesis and overall immune homeostasis. Unfortunately, the thymus is highly susceptible to stress-induced acute Involution. Prolonged thymus atrophy in stress situations can contribute to peripheral T cell deficiency or inhibit immune reconstitution. Little is known, however, about specific roles for leptin signaling in the thymus or the underlying mechanisms driving Thymic Involution or Thymic recovery after acute stress. We report here that leptin receptor expression is restricted in thymus to medullary epithelial cells. Using a model of endotoxemia-induced acute Thymic Involution and recovery, we have demonstrated a role for supraphysiologic leptin in protection of Thymic epithelial cells (TECs). We also present data in support of our hypothesis that leptin treatment decreases in vivo endotoxemia-induced apoptosis of double positive thymocytes and promotes proliferation of double negative thymocytes through a leptin receptor isoform b-specific mechanism. Furthermore, our studies have revealed that leptin treatment increases Thymic expression of interleukin-7, an important soluble thymocyte growth factor produced by medullary TECs. Taken together, these studies support an intraThymic role for the metabolic hormone leptin in maintaining healthy Thymic epithelium and promoting thymopoiesis, which is revealed when thymus homeostasis is perturbed by endotoxemia.
Diana M Lopez - One of the best experts on this subject based on the ideXlab platform.
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downregulation of interleukin 7 and hepatocyte growth factor in the Thymic microenvironment is associated with thymus Involution in tumor bearing mice
Cancer Immunology Immunotherapy, 2009Co-Authors: Roberto Carrio, Norman H Altman, Diana M LopezAbstract:During mammary tumorigenesis, there is a profound Thymic Involution associated with severe depletion of the most abundant subset of thymocytes, CD4+CD8+ immature cells, and an early arrest in at least two steps of T cell differentiation. Thymic atrophy that is normally related with aging has been observed in other model systems, including graft-vs-host disease (GVHD) and tumor development. However, the mechanisms involved in this phenomenon remain to be elucidated. Vascular endothelial growth factor (VEGF) has been associated with Thymic Involution, when expressed at high levels systemically. In thymuses of D1-DMBA-3 tumor-bearing mice, this growth factor is diminished relative to the level of normal thymuses. Interestingly, the expression of hepatocyte growth factor (HGF), which has been associated with proliferation, cell survival, angiogenesis and B-cell differentiation, is profoundly down-regulated in thymuses of tumor bearers. In parallel, IL-7 and IL-15 mRNA, crucial cytokines involved in thymocytes development and cellular homeostasis, respectively, are also down-regulated in the thymuses of tumor hosts as compared to those of normal mice. Injection of HGF into mice implanted with mammary tumors resulted in normalization of Thymic volume and levels of VEGF, IL-7 and IL-15. While, injections of IL-7 partially restored the Thymic Involution observed in the thymuses of tumor-bearing mice, injection of IL-15 did not have any significant effects. Our data suggest that the downregulation of HGF and IL-7 may play an important role in the Thymic Involution observed in tumor-bearing hosts.
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early block in maturation is associated with Thymic Involution in mammary tumor bearing mice
Journal of Immunology, 2000Co-Authors: Becky Adkins, Vijaya Charyulu, Qi Ling Sun, David Lobo, Diana M LopezAbstract:We previously reported that mice implanted with mammary tumors show a progressive Thymic Involution that parallels the growth of the tumor. The Involution is associated with a severe depletion of CD4+8+ thymocytes. We have investigated three possible mechanisms leading to this Thymic atrophy: 1) increased apoptosis, 2) decreased proliferation, and 3) disruption of normal Thymic maturation. The levels of Thymic apoptosis were determined by propidium iodide and annexin V staining. A statistically significant, but minor, increase in Thymic apoptosis in tumor-bearing mice was detected with propidium iodide and annexin V staining. The levels of proliferation were assessed by in vivo labeling with 5′-bromo-2′-deoxyuridine (BrdU). The percentages of total thymocytes labeled 1 day following BrdU injection were similar in control and tumor-bearing mice. Moreover, the percentages of CD4−8− thymocytes that incorporated BrdU during a short term pulse (5 h) of BrdU were similar. Lastly, Thymic maturation was evaluated by examining CD44 and CD25 expression among CD4−8− thymocytes. The percentage of CD44+ cells increased, while the percentage of CD25+ cells decreased among CD4−8− thymocytes from tumor-bearing vs control animals. Together, these findings suggest that the Thymic hypocellularity seen in mammary tumor bearers is not due to a decreased level of proliferation, but, rather, to an arrest at an early stage of Thymic differentiation along with a moderate increase in apoptosis.
Jochen Huehn - One of the best experts on this subject based on the ideXlab platform.
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influenza a virus induced thymus atrophy differentially affects dynamics of conventional and regulatory t cell development in mice
European Journal of Immunology, 2021Co-Authors: Yassin Elfaki, Philippe Robert, Christoph Binz, Christine S. Falk, Dunja Bruder, Immo Prinz, Stefan Floess, Michael Meyerhermann, Jochen HuehnAbstract:Foxp3+ Treg cells, which are crucial for maintenance of self-tolerance, mainly develop within the thymus, where they arise from CD25+ Foxp3- or CD25- Foxp3+ Treg cell precursors. Although it is known that infections can cause transient Thymic Involution, the impact of infection-induced thymus atrophy on Thymic Treg (tTreg) cell development is unknown. Here, we infected mice with influenza A virus (IAV) and studied thymocyte population dynamics post infection. IAV infection caused a massive, but transient Thymic Involution, dominated by a loss of CD4+ CD8+ double-positive (DP) thymocytes, which was accompanied by a significant increase in the frequency of CD25+ Foxp3+ tTreg cells. Differential apoptosis susceptibility could be experimentally excluded as a reason for the relative tTreg cell increase, and mathematical modeling suggested that enhanced tTreg cell generation cannot explain the increased frequency of tTreg cells. Yet, an increased death of DP thymocytes and augmented exit of single-positive (SP) thymocytes was suggested to be causative. Interestingly, IAV-induced thymus atrophy resulted in a significantly reduced T-cell receptor (TCR) repertoire diversity of newly produced tTreg cells. Taken together, IAV-induced thymus atrophy is substantially altering the dynamics of major thymocyte populations, finally resulting in a relative increase of tTreg cells with an altered TCR repertoire.
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Influenza A virus-induced thymus atrophy differentially affects dynamics of conventional and regulatory T cell development
2020Co-Authors: Yassin Elfaki, Philippe Robert, Christoph Binz, Christine S. Falk, Dunja Bruder, Immo Prinz, Stefan Floess, Michael Meyer-hermann, Jochen HuehnAbstract:ABSTRACT Foxp3+ regulatory T (Treg) cells, which are crucial for maintenance of self-tolerance, mainly develop within the thymus, where they arise from CD25+Foxp3− or CD25−Foxp3+ Treg cell precursors. Although it is known that infections can cause transient Thymic Involution, the impact of infection-induced thymus atrophy on Thymic Treg (tTreg) cell development is unknown. Here, we infected mice with influenza A virus (IAV) and studied thymocyte population dynamics post infection. IAV infection caused a massive, but transient Thymic Involution, dominated by a loss of CD4+CD8+ double-positive (DP) thymocytes, which was accompanied by a significant increase in the frequency of CD25+Foxp3+ tTreg cells. Differential apoptosis susceptibility could be experimentally excluded as a reason for the relative tTreg cell increase, and mathematical modeling suggested that enhanced tTreg cell generation cannot explain the increased frequency of tTreg cells. Yet, an increased death of DP thymocytes and augmented exit of single-positive (SP) thymocytes was suggested to be causative. Interestingly, IAV-induced thymus atrophy resulted in a significantly reduced T cell receptor (TCR) repertoire diversity of newly produced tTreg cells. Taken together, IAV-induced thymus atrophy is substantially altering the dynamics of major thymocyte populations, finally resulting in a relative increase of tTreg cells with an altered TCR repertoire.
Amanda L Gruver - One of the best experts on this subject based on the ideXlab platform.
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Acute Endotoxin-Induced Thymic Atrophy Is Characterized By IntraThymic Inflammatory and Wound Healing Responses
2016Co-Authors: Matthew J Billard, Amanda L Gruver, Gregory D SempowskiAbstract:Background: Productive thymopoiesis is essential for a robust and healthy immune system. Thymus unfortunately is acutely sensitive to stress resulting in Involution and decreased T cell production. Thymic Involution is a complication of many clinical settings, including infection, malnutrition, starvation, and irradiation or immunosuppressive therapies. Systemic rises in glucocorticoids and inflammatory cytokines are known to contribute to Thymic atrophy. Little is known, however, about intraThymic mechanisms that may actively contribute to thymus atrophy or initiate Thymic recovery following stress events. Methodology/Principal Findings: Phenotypic, histologic and transcriptome/pathway analysis of murine Thymic tissue during the early stages of endotoxemia-induced Thymic Involution was performed to identify putative mechanisms that drive Thymic Involution during stress. Thymus atrophy in this murine model was confirmed by down-regulation of genes involved in T cell development, cell activation, and cell cycle progression, correlating with observed phenotypic and histologic thymus Involution. Significant gene changes support the hypothesis that multiple key intraThymic pathways are differentially activated during stress-induced Thymic Involution. These included direct activation of thymus tissue by LPS through TLR signaling, local expression of inflammatory cytokines, inhibition of T cell signaling, and induction of wound healing/tissue remodeling. Conclusions/Significance: Taken together, these observations demonstrated that in addition to the classic systemi
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acute endotoxin induced Thymic atrophy is characterized by intraThymic inflammatory and wound healing responses
PLOS ONE, 2011Co-Authors: Matthew J Billard, Amanda L Gruver, Gregory D SempowskiAbstract:Background Productive thymopoiesis is essential for a robust and healthy immune system. Thymus unfortunately is acutely sensitive to stress resulting in Involution and decreased T cell production. Thymic Involution is a complication of many clinical settings, including infection, malnutrition, starvation, and irradiation or immunosuppressive therapies. Systemic rises in glucocorticoids and inflammatory cytokines are known to contribute to Thymic atrophy. Little is known, however, about intraThymic mechanisms that may actively contribute to thymus atrophy or initiate Thymic recovery following stress events.
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leptin receptor is expressed in thymus medulla and leptin protects against Thymic remodeling during endotoxemia induced thymus Involution
Journal of Endocrinology, 2009Co-Authors: Amanda L Gruver, Melissa S Ventevogel, Gregory D SempowskiAbstract:Leptin deficiency in mice results in chronic Thymic atrophy, suppressed cell-mediated immunity, and decreased numbers of total lymphocytes, suggesting a key role for the metabolic hormone leptin in regulating thymopoiesis and overall immune homeostasis. Unfortunately, the thymus is highly susceptible to stress-induced acute Involution. Prolonged thymus atrophy in stress situations can contribute to peripheral T cell deficiency or inhibit immune reconstitution. Little is known, however, about specific roles for leptin signaling in the thymus or the underlying mechanisms driving Thymic Involution or Thymic recovery after acute stress. We report here that leptin receptor expression is restricted in thymus to medullary epithelial cells. Using a model of endotoxemia-induced acute Thymic Involution and recovery, we have demonstrated a role for supraphysiologic leptin in protection of Thymic epithelial cells (TECs). We also present data in support of our hypothesis that leptin treatment decreases in vivo endotoxemia-induced apoptosis of double positive thymocytes and promotes proliferation of double negative thymocytes through a leptin receptor isoform b-specific mechanism. Furthermore, our studies have revealed that leptin treatment increases Thymic expression of interleukin-7, an important soluble thymocyte growth factor produced by medullary TECs. Taken together, these studies support an intraThymic role for the metabolic hormone leptin in maintaining healthy Thymic epithelium and promoting thymopoiesis, which is revealed when thymus homeostasis is perturbed by endotoxemia.
Clare C. Blackburn - One of the best experts on this subject based on the ideXlab platform.
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Thymic Involution and rising disease incidence with age
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Clare C. Blackburn, Sam Palmer, Luca Albergante, T J NewmanAbstract:For many cancer types, incidence rises rapidly with age as an apparent power law, supporting the idea that cancer is caused by a gradual accumulation of genetic mutations. Similarly, the incidence of many infectious diseases strongly increases with age. Here, combining data from immunology and epidemiology, we show that many of these dramatic age-related increases in incidence can be modeled based on immune system decline, rather than mutation accumulation. In humans, the thymus atrophies from infancy, resulting in an exponential decline in T cell production with a half-life of ∼16 years, which we use as the basis for a minimal mathematical model of disease incidence. Our model outperforms the power law model with the same number of fitting parameters in describing cancer incidence data across a wide spectrum of different cancers, and provides excellent fits to infectious disease data. This framework provides mechanistic insight into cancer emergence, suggesting that age-related decline in T cell output is a major risk factor.
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Foxn1 Is Dynamically Regulated in Thymic Epithelial Cells during Embryogenesis and at the Onset of Thymic Involution
2016Co-Authors: Kathy E. O’neill, Craig S. Nowell, Frances H. Stenhouse, Nicholas Bredenkamp, Christin Tischner, Harsh J. Vaidya, Diana C. Peddie, Terri Gaskell, Clare C. BlackburnAbstract:Thymus function requires extensive cross-talk between developing T-cells and the Thymic epithelium, which consists of cortical and medullary TEC. The transcription factor FOXN1 is the master regulator of TEC differentiation and function, and declining Foxn1 expression with age results in stereotypical Thymic Involution. Understanding of the dynamics of Foxn1 expression is, however, limited by a lack of single cell resolution data. We have generated a novel reporter of Foxn1 expression, Foxn1G, to monitor changes in Foxn1 expression during embryogenesis and Involution. Our data reveal that early differentiation and maturation of cortical and medullary TEC coincides with precise sub-lineage-specific regulation of Foxn1 expression levels. We further show that initiation of Thymic Involution is associated with reduced cTEC functionality, and proportional expansion of FOXN1-negative TEC in both cortical and medullary sub-lineages. Cortex-specific down-regulation of Foxn1 between 1 and 3 months of age may therefore be a key driver of the early stages of age-related Thymic Involution.
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regeneration of the aged thymus by a single transcription factor
Development, 2014Co-Authors: Nicholas Bredenkamp, Craig S. Nowell, Clare C. BlackburnAbstract:Thymic Involution is central to the decline in immune system function that occurs with age. By regenerating the thymus, it may therefore be possible to improve the ability of the aged immune system to respond to novel antigens. Recently, diminished expression of the Thymic epithelial cell (TEC)-specific transcription factor Forkhead box N1 (FOXN1) has been implicated as a component of the mechanism regulating age-related Involution. The effects of upregulating FOXN1 function in the aged thymus are, however, unknown. Here, we show that forced, TEC-specific upregulation of FOXN1 in the fully involuted thymus of aged mice results in robust thymus regeneration characterized by increased thymopoiesis and increased naive T cell output. We demonstrate that the regenerated organ closely resembles the juvenile thymus in terms of architecture and gene expression profile, and further show that this FOXN1-mediated regeneration stems from an enlarged TEC compartment, rebuilt from progenitor TECs. Collectively, our data establish that upregulation of a single transcription factor can substantially reverse age-related Thymic Involution, identifying FOXN1 as a specific target for improving thymus function and, thus, immune competence in patients. More widely, they demonstrate that organ regeneration in an aged mammal can be directed by manipulation of a single transcription factor, providing a provocative paradigm that may be of broad impact for regenerative biology.
