| dc.identifier.uri | http://hdl.handle.net/11401/76479 | |
| dc.description.sponsorship | This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. | en_US |
| dc.format | Monograph | |
| dc.format.medium | Electronic Resource | en_US |
| dc.language.iso | en_US | |
| dc.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dc.type | Dissertation | |
| dcterms.abstract | Control of immune responses is vital for maintenance of homeostasis. The immune system must be able to quickly respond to invading pathogens, while suppressing responses that could lead to autoimmunity and inflammation. Recent advances have revealed a role for the nervous system in maintaining homeostasis. In the prototypical neural reflex, during activation of the inflammatory reflex, vagus nerve signaling culminates on adrenergic signals translated to acetylcholine release by splenic T lymphocytes which activate receptor signals on macrophages to attenuate cytokine release. Many additional interactions remain to be elucidated. Herein, several novel immune-nervous interactions are characterized. A newly-described neuronal reflex, which regulates antigen flow through the lymphatic system is described. Antigen flow through the lymphatic system is restricted when an animal has been immunized against it. We utilized fluorescently-labeled antigen imaged in situ in the lymphatic system, and found that neuronal interventions were able to modulate antigen localization. Antigen trafficking that is normally restricted in immunized mice was restored when nerve activity was blocked pharmaceutically or by genetically-driven neuron depletion. In addition, induction of neuronal activity restricted antigen in naïve mice. This establishes a role for neurons in alteration of lymphatic trafficking and provides a new way for bioelectronic intervention to modulate immune function. Vagus nerve stimulation inhibits inflammatory responses and modulates B cell antibody production. Galantamine, a centrally-acting acetylcholinesterase inhibitor is known to signal through the vagus nerve. Herein, use of this compound is shown to delay the onset of type 1 diabetes in a non-obese diabetic mouse model while inhibiting immune responses in a disease-specific manner. Daily administration of galantamine delayed the onset of hyperglycemia and insulitis, and decreased anti-insulin antibodies. These findings highlight a previously unrecognized anti-inflammatory effect of galantamine in preclinical type I diabetes. Blood pressure is mediated by cholinergic signaling; however, the vasculature lacks cholinergic neurons. The source of acetylcholine has not yet been described. Acetylcholine-producing T cells are herein described as being necessary and vital to maintenance of blood pressure. To support this study, I produced a T cell line that overproduces ChAT. The functional role of TChAT is verified using in vivo mouse studies of blood pressure variation in different phenotypic backgrounds. This new role for T cells acting as interneurons expands our understanding of the role of the immune system. In addition, these T cells increase cholinergic signaling in response to β2-adrenergic receptor ligand binding. Until now, study of specific T cell responses to β2-adrenergic receptor activation in vivo has been impossible as numerous other cell types also respond to β2-adrenergic receptor. A novel use of optogenetic technology allows study of these cells, utilizing light to activate receptors temporally and spatially in lieu of adrenergic ligands. T cells were genetically modified to express a chimeric fusion of the β2-adrenergic receptor and bovine rhodopsin. Optogenetic activation was verified to activate intracellular pathways, and modulate T cell cytokine responses. This tool will allow further study into the role of immune cells as part of neural pathways, and could provide new treatment modalities. Understanding the interactions of these two systems is vital to the newly-developing field of bioelectronic medicine, which promises to treat disease by modulating electrical signals of the nerves throughout the body. The examples provided herein are important pieces of the overall puzzle that will provide new therapeutic interventions. | |
| dcterms.abstract | Control of immune responses is vital for maintenance of homeostasis. The immune system must be able to quickly respond to invading pathogens, while suppressing responses that could lead to autoimmunity and inflammation. Recent advances have revealed a role for the nervous system in maintaining homeostasis. In the prototypical neural reflex, during activation of the inflammatory reflex, vagus nerve signaling culminates on adrenergic signals translated to acetylcholine release by splenic T lymphocytes which activate receptor signals on macrophages to attenuate cytokine release. Many additional interactions remain to be elucidated. Herein, several novel immune-nervous interactions are characterized. A newly-described neuronal reflex, which regulates antigen flow through the lymphatic system is described. Antigen flow through the lymphatic system is restricted when an animal has been immunized against it. We utilized fluorescently-labeled antigen imaged in situ in the lymphatic system, and found that neuronal interventions were able to modulate antigen localization. Antigen trafficking that is normally restricted in immunized mice was restored when nerve activity was blocked pharmaceutically or by genetically-driven neuron depletion. In addition, induction of neuronal activity restricted antigen in naïve mice. This establishes a role for neurons in alteration of lymphatic trafficking and provides a new way for bioelectronic intervention to modulate immune function. Vagus nerve stimulation inhibits inflammatory responses and modulates B cell antibody production. Galantamine, a centrally-acting acetylcholinesterase inhibitor is known to signal through the vagus nerve. Herein, use of this compound is shown to delay the onset of type 1 diabetes in a non-obese diabetic mouse model while inhibiting immune responses in a disease-specific manner. Daily administration of galantamine delayed the onset of hyperglycemia and insulitis, and decreased anti-insulin antibodies. These findings highlight a previously unrecognized anti-inflammatory effect of galantamine in preclinical type I diabetes. Blood pressure is mediated by cholinergic signaling; however, the vasculature lacks cholinergic neurons. The source of acetylcholine has not yet been described. Acetylcholine-producing T cells are herein described as being necessary and vital to maintenance of blood pressure. To support this study, I produced a T cell line that overproduces ChAT. The functional role of TChAT is verified using in vivo mouse studies of blood pressure variation in different phenotypic backgrounds. This new role for T cells acting as interneurons expands our understanding of the role of the immune system. In addition, these T cells increase cholinergic signaling in response to β2-adrenergic receptor ligand binding. Until now, study of specific T cell responses to β2-adrenergic receptor activation in vivo has been impossible as numerous other cell types also respond to β2-adrenergic receptor. A novel use of optogenetic technology allows study of these cells, utilizing light to activate receptors temporally and spatially in lieu of adrenergic ligands. T cells were genetically modified to express a chimeric fusion of the β2-adrenergic receptor and bovine rhodopsin. Optogenetic activation was verified to activate intracellular pathways, and modulate T cell cytokine responses. This tool will allow further study into the role of immune cells as part of neural pathways, and could provide new treatment modalities. Understanding the interactions of these two systems is vital to the newly-developing field of bioelectronic medicine, which promises to treat disease by modulating electrical signals of the nerves throughout the body. The examples provided herein are important pieces of the overall puzzle that will provide new therapeutic interventions. | |
| dcterms.available | 2017-09-20T16:50:22Z | |
| dcterms.contributor | Tracey, Kevin J | en_US |
| dcterms.contributor | Reich, Nancy | en_US |
| dcterms.contributor | Sherry, Barbara | en_US |
| dcterms.contributor | Carpino, Nicholas | en_US |
| dcterms.contributor | Andersson, Ulf. | en_US |
| dcterms.creator | Hanes, William Michael | |
| dcterms.dateAccepted | 2017-09-20T16:50:22Z | |
| dcterms.dateSubmitted | 2017-09-20T16:50:22Z | |
| dcterms.description | Department of Molecular and Cellular Biology. | en_US |
| dcterms.extent | 155 pg. | en_US |
| dcterms.format | Application/PDF | en_US |
| dcterms.format | Monograph | |
| dcterms.identifier | http://hdl.handle.net/11401/76479 | |
| dcterms.issued | 2015-05-01 | |
| dcterms.language | en_US | |
| dcterms.provenance | Made available in DSpace on 2017-09-20T16:50:22Z (GMT). No. of bitstreams: 1
Hanes_grad.sunysb_0771E_12642.pdf: 2325868 bytes, checksum: 388c404deb29d9ba0d9298abab6e4504 (MD5)
Previous issue date: 2015 | en |
| dcterms.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dcterms.subject | antigen trafficking, bioelectronic medicine, immune response regulation, lymph nodes, neurons, optogenetics | |
| dcterms.subject | Immunology | |
| dcterms.title | Neuronal Control of Immunity | |
| dcterms.type | Dissertation | |
