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dc.contributor.advisor Sempowski, Gregory D en_US
dc.contributor.author Gruver, Amanda Louise en_US
dc.date.accessioned 2009-08-27T18:21:18Z
dc.date.available 2011-08-27T04:30:07Z
dc.date.issued 2009 en_US
dc.identifier.uri http://hdl.handle.net/10161/1293
dc.description Dissertation en_US
dc.description.abstract <p>Thymus atrophy is highly inducible by stress and prolonged thymus atrophy can contribute to T cell deficiency or inhibit immune recovery after acute peripheral T cell depletion. Little is known regarding the mechanisms driving thymic involution or thymic reconstitution after acute stress. Leptin deficiency in mice results in chronic thymic atrophy, suppressed cell-mediated immunity, and decreased numbers of total lymphocytes, suggesting a role for leptin in regulating thymopoiesis and overall immune homeostasis. Exogenous leptin administration during stress has been shown to protect against thymic damage, yet the mechanisms governing these thymostimulatory effects are currently undefined. Studies herein define the impact of endotoxin-induced thymic damage in the stromal and lymphoid compartment of the thymus and systemic glucocorticoid and cytokine responses in the animal. We report here the novel finding that leptin receptor expression is restricted to medullary thymic epithelial cells in the normal thymus. Using a model of endotoxin-induced acute thymic involution and recovery, we have demonstrated a role for the metabolic hormone leptin in protection of medullary thymic epithelial cells from acute endotoxin-induced damage. We also demonstrated that systemic leptin treatment decreased endotoxin-induced apoptosis of double positive thymocytes and promoted proliferation of double negative thymocytes in vivo through a leptin receptor isoform b-specific mechanism. Leptin treatment increased thymic expression of IL-7, an important soluble thymocyte growth factor produced by medullary thymic epithelial cells. We also found leptin to inhibit systemic glucocorticoid and pro-inflammatory cytokine responses. Using leptin-deficient and leptin receptor-deficient mice in our stress model, we found that endotoxin-induced thymic atrophy was exacerbated in the absence of leptin, despite an inability to mount a proper pro-inflammatory cytokine response. Together, these data support a model in which leptin can function to protect the thymus gland from stress-induced acute damage in part by reduction of systemic corticosteroid and pro-inflammatory cytokine responses, and intrathymically through a mechanism orchestrated by medullary thymic epithelial cells and their soluble mediators (e.g. IL-7). Taken together, these studies suggest a physiological role for leptin signaling in the thymus for maintaining healthy thymic epithelium and promoting thymopoiesis, which is revealed when thymus homeostasis is perturbed by stress.</p> en_US
dc.format.extent 4326221 bytes
dc.format.mimetype application/pdf
dc.language.iso en_US
dc.subject Health Sciences, Immunology en_US
dc.subject Health Sciences, Pathology en_US
dc.subject Leptin en_US
dc.subject Leptin Receptor en_US
dc.subject Lipopolysaccharide en_US
dc.subject Thymic Atrophy en_US
dc.subject Thymopoiesis en_US
dc.subject Thymus en_US
dc.title Leptin Regulation of Thymopoiesis During Endotoxin-Induced Acute Thymic Atrophy en_US
dc.type Dissertation en_US
dc.department Pathology en_US
duke.embargo.months 24 en_US

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