La Rocca, Claudia (2014) In vivo effects of metreleptin treatment on immune system of females with acquired hypoleptinemia. [Tesi di dottorato]

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Leptin, a peptide hormone secreted by adipocytes in proportion of the amount of energy stored in fat, plays a central role in regulating human energy homeostasis, controlling food intake, reproductive and immune functions. As a cytokine, leptin can affect thymic homeostasis and the secretion of acute-phase reactants such as interleukin-1 and tumour-necrosis factor (1). Decreased levels of leptin, also known as hypoleptinemia, signal to the brain a state of energy deprivation. Hypoleptinemia can be a congenital or acquired condition, and is associated with alterations of several neuroendocrine axes, including the hypothalamic-pituitary-gonadal, -thyroid, -growth hormone, and -adrenal axes (2). A model of acquired chronic hypoleptinemia induced by negative energy balance is the hypothalamic amenorrhea (HA), previously it has been demonstrated that hypoleptinemia underlies the dysfunction of neuroendocrine axes and bone metabolism associated with HA (3). In uncontrolled human studies, low leptin levels are associated with impaired immune responses and reduced T cell counts but effects of leptin replacement on the adaptive immune system have not yet been reported in the context of randomized controlled studies and/or in conditions of chronic, acquired leptin deficiency. To address these questions, we performed the first randomized, double-blinded, placebo-controlled trial of recombinant methionyl-human-leptin (metreleptin) administration in replacement doses over 36 weeks in women with HA. Metreleptin restored both CD4+ T cell counts and their in vitro proliferative responses, these changes were accompanied by a transcriptional signature where relevant genes of cell survival and hormonal response were up-regulated and apoptosis genes were down-regulated in circulating immune cells. We also observed that signaling pathways of cell growth/survival/proliferation were directly activated by acute in vivo metreleptin administration in subjects with both chronic hypoleptinemia and normoleptinemic lean female subjects. These data show that metreleptin administration, in doses that normalize circulating leptin levels, induce transcriptional changes, activate intracellular signaling pathways and restore CD4+ T cell counts. Thus, metreleptin may prove to be a safe and effective therapy for selective CD4+ T cell immune-reconstitution in hypoleptinemic states associated with cachexia such as tuberculosis and HIV infection in which CD4+ T cells are reduced.

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