The Neuroimmunological Consequences of Spinal Cord Injury

The Neuroimmunological Consequences of Spinal Cord Injury

Bibliographic Details
Main Author: Carpenter, Randall Scott
Language:English
Published: The Ohio State University / OhioLINK 2019
Subjects:
Neurosciences
Neurobiology
Immunology
Biomedical Research
spinal cord injury
neuroimmunology
neuroinflammation
neurotrauma
humanized mice
hematopoiesis
bone marrow
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=osu1562674460866325
id ndltd-OhioLink-oai-etd.ohiolink.edu-osu1562674460866325
record_format oai_dc
collection NDLTD
language English
sources NDLTD
topic Neurosciences
Neurobiology
Immunology
Biomedical Research
spinal cord injury
neuroimmunology
neuroinflammation
neurotrauma
humanized mice
hematopoiesis
bone marrow
spellingShingle Neurosciences
Neurobiology
Immunology
Biomedical Research
spinal cord injury
neuroimmunology
neuroinflammation
neurotrauma
humanized mice
hematopoiesis
bone marrow
Carpenter, Randall Scott
The Neuroimmunological Consequences of Spinal Cord Injury
author Carpenter, Randall Scott
author_facet Carpenter, Randall Scott
author_sort Carpenter, Randall Scott
title The Neuroimmunological Consequences of Spinal Cord Injury
title_short The Neuroimmunological Consequences of Spinal Cord Injury
title_full The Neuroimmunological Consequences of Spinal Cord Injury
title_fullStr The Neuroimmunological Consequences of Spinal Cord Injury
title_full_unstemmed The Neuroimmunological Consequences of Spinal Cord Injury
title_sort neuroimmunological consequences of spinal cord injury
publisher The Ohio State University / OhioLINK
publishDate 2019
url http://rave.ohiolink.edu/etdc/view?acc_num=osu1562674460866325
work_keys_str_mv AT carpenterrandallscott theneuroimmunologicalconsequencesofspinalcordinjury
AT carpenterrandallscott neuroimmunologicalconsequencesofspinalcordinjury
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-osu15626744608663252021-08-03T07:11:43Z The Neuroimmunological Consequences of Spinal Cord Injury Carpenter, Randall Scott Neurosciences Neurobiology Immunology Biomedical Research spinal cord injury neuroimmunology neuroinflammation neurotrauma humanized mice hematopoiesis bone marrow <p>Spinal cord injury (SCI) is a devastating condition causing severe loss of motor, sensory, and autonomic function below where the injury occurs. injury the cord causes severe damage to cell components, blood-spinal cord barrier, and axon tracts. However, SCI also causes hemorrhage and the release of cell content that initiate a secondary wave of inflammation and additional tissue damage. Therefore, targeting the immune system acutely after injury may prevent further damage to the cord. However, components of the neuroinflammatory response are also beneficial for spinal cord repair long-term. A deeper understanding of these divergent aspects of post-SCI inflammation and immune function could aid in the development of therapies that modulate immune responses to be less damaging while promoting their reparative properties.<p>Translating promising therapeutics from bench to bedside has been historically grim in the context of central nervous system (CNS) injury and disease. Within the context of neuroimmunology, there are many differences in the immune systems of rodents and humans that may preclude the translation of therapeutic strategies, warranting a further understanding of the human immune response to SCI. However, studies involving human or large animal models are prohibitively expensive, difficult to perform, and preclude in vivo mechanistic studies. Novel models of human immune function within the context of CNS injury and disease are warranted.<p>Humanized mice are immunocompromised mice engrafted with human immune systems, creating an in vivo model of human immune function. The premise of humanized mice originally came from a need to model HIV infection. Humanized mice have since allowed for the investigation of human immunobiology in the context of hematopoiesis, immunotherapy, immune-oncology, and infectious disease. Humanized mice represent a promising tool to model human immune responses to CNS injury and disease, including SCI. The first section of this dissertation focuses on incorporating humanized mice into a pre-clinical spinal cord injury research program and is split into two components. First, I demonstrated the feasibility of performing SCI research on humanized mice. Standard post-injury assessment of hindlimb locomotor function, human immune cell responses, and lesion pathology were performed. I show that humanized mice have nearly identical post-SCI lesion development and neurological recovery to traditional (immunocompetent) mouse models. However, humanized mice have worse lesion pathology and functional recovery compared to a cohort of non-engrafted immunocompromised mice.<p>In the second part I demonstrate that time post-engraftment is a critical factor in the development of the human immune system in these mice. Human immune system development is limited 2 months post-engraftment, resulting in an underwhelming human immune response after SCI. However, waiting until 4 months post-engraftment improves human immune responses to SCI. I also demonstrate that the human immune system retains important immunological functions when stimulated both in vivo and ex vivo. Finally, I show for the first time that human T cells and human macrophages contact each other within the injury epicenter in a way that resembles the formation of functional “immune synapses”. Overall, these data are critical for others to be able to correctly integrate humanized mice into their research paradigms.<p>The second section of this dissertation focuses on post-SCI immune dysfunction. Infectious complications are a significant contributor to morbidity and mortality after SCI. Infections also limit the extent of neurological recovery compared to patients without infections. Third, infectious complications cause nearly a third of SCI individuals to be re-hospitalized every year, with a median hospital stay of 22 days that results in extensive medical costs. Thus, understanding immune system dysfunction is of critical importance to individuals living with SCI.<p>Hematopoiesis is the generation of mature immune cells in the bone marrow from hematopoietic stem and progenitor cells (HSPCs). Other than B cell progenitors, no pre-clinical studies have determined how SCI may influence HSPC responses after injury. However, clinical data demonstrates that the number, proliferation, and function of HSPCs is significantly altered in bone marrow of SCI patients. Therefore, I focus the second part of this dissertation on the effects of high-thoracic SCI on bone marrow HSPC and mature immune responses. Specifically, I show that SCI causes excessive HSPC proliferation and myeloid biasing, while also impairing the mobilization of HSPCs and mature lymphocytes. Importantly, these differences last chronically after SCI, being recapitulated after innate immune challenge. Using ex vivo assays, I also demonstrate that HSPC function is permanently impaired after high-thoracic SCI. Lastly, impaired HSPC and lymphocyte mobilization after SCI is due to dysregulated chemotactic signaling in bone marrow, which can be reversed with pharmacological intervention to restore extramedullary hematopoiesis and adaptive immune surveillance.<p>The goal of this dissertation is to provide new insights into the neuroimmunological consequences of spinal cord injury. Because my work spans both neuroinflammation and immune dysfunction, I’ve split the dissertation into two complementary sections focusing on data in each. In all, I hope this document highlights the complex relationship between the nervous and immune systems, and how these systems interact in the context of CNS injury. 2019-10-02 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1562674460866325 http://rave.ohiolink.edu/etdc/view?acc_num=osu1562674460866325 restricted--full text unavailable until 2022-08-05 This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

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