Medicine and Health Sciences Commons^™

Development Of New Treatments For Asthma And Neuropathic Pain Based On Ɣ-Aminobutyric Acid A Receptor (Gabaar) Ligands, Nicolas Mark Zahn

Theses and Dissertations

The γ-aminobutyric acid A receptor (GABAAR) is a ligand-gated pentameric chloride channel consisting of several identified subunits: α1-6, β1-3, γ1-3, δ, ε, π, θ, ρ1-3.1-2 Typical arrangement of subunits consists of two α subunits, two β subunits, and one γ subunit.3 GABAARs have two binding sites for the endogenous ligand γ-aminobutyric acid (GABA), between the α and β subunits. GABAARs also have a binding site for positive allosteric modulators, such as benzodiazepines, between the α and γ subunits.4-5 Due to their ability to treat anxiety, epilepsy, insomnia, and muscle relaxation, benzodiazepines are widely prescribed pharmaceuticals.6-7 Still, adverse effects result from …

Effect Of Regulatory T Cells On The Humoral Immune Response To Borrelia Burgdorferi, Tanya Kozlik

Theses and Dissertations

Lyme borreliosis, caused by the bacteria Borrelia burgdorferi, is the most common tick-borne disease in the United States. Difficulties and delays in diagnosing can leave patients with long-term illness affecting multiple body systems. Therefore, understanding the immunomodulatory mechanisms affecting disease pathology will aid in the development of therapeutics and/or a safe, effective vaccine. In this thesis, we aimed to test the hypothesis that depletion of regulatory T cells amplifies the humoral response to Borrelia burgdorferi but leads to worsened clinical manifestations. To test this hypothesis, “depletion of regulatory T cell” (“DEREG”) BALB/c mice were depleted of Treg cells prior to …

Characterization Of The Effect Of Photobiomodulation On Peripheral Blood Mononuclear Cells And Cd4+ T Cells From Healthy Donors And Multiple Sclerosis Subjects., Miguel Tolentino

Theses and Dissertations

Multiple Sclerosis (MS) is a CD4+ T cell-mediated autoimmune demyelinating disease. The pathogenesis of MS is a combination of a pro-inflammatory autoimmune response coupled with nitrosative and oxidative stress. Mitochondrial dysfunction within the central nervous system (CNS) leads to a reduction of ATP and high concentrations of nitric oxide leads to the production of reactive oxygen and nitrogen species (ROS and RNS), resulting in oxidative and nitrosative stress that damages myelin and axons, leading to axonal loss and disease progression. Nitrosative stress is present in MS even in early stages of disease even before inflammation and the myelin destruction. The …

Functional Characterization Of Lt-Hsc Metabolic Activity Dependent On Ahr Activity, Everett Tate

Theses and Dissertations

The cells of the immune system are descended from multipotent hematopoietic stem cells (HSCs) that emerge during development. Multipotency means that a single progenitor HSC can differentiate into any cell of the immune system. HSCs are required to do this for the lifetime of the organism through a process called self-renewal, and as such, any perturbation during development or in the bone marrow can have a trickle-down effect, affecting the self-renewal capacity or ability to terminally differentiate. The aryl hydrocarbon receptor (AHR) is a known regulator of HSCs. The AHR is a transcription factor required for the detoxification of numerous …

Role Of Regulatory T Cells In The Development And Progression Of Lyme Disease In Balb/C Mice, Kaitlyn Nielsen

Theses and Dissertations

Lyme disease, caused by Borrelia burgdorferi, is an increasingly important public health concern, with tens of thousands of new cases being diagnosed each year, even in previously non-endemic areas. It is known that symptoms of Lyme disease are caused by an inflammatory immune response initiated to aid in clearance of the pathogen. Left unchecked, these inflammatory responses can potentially increase tissue damage, leading to increased disease severity. Mechanisms responsible for the control of the inflammatory response to infection with B. burgdorferi are not entirely understood. Evidence exists that regulatory T (Treg) cells, a population of Foxp3-expressing CD4+ T cells known …

Differential Migration Of Cd4+ And Cd8+ T Cells During An Immune Response, Jacob Parrott

Theses and Dissertations

ABSTRACT

DIFFERENTIAL MIGRATION OF CD4+ AND CD8+ T CELLS DURING AN IMMUNE RESPONSE

by

Jacob Parrott

The University of Wisconsin-Milwaukee, 2018

Under the Supervision of Professor Douglas Steeber

Lymphocyte migration is critical for recognizing pathogenic challenges in a timely manner and generating effective, rapid immune responses. Lymphocyte numbers in secondary lymphoid tissues such as lymph nodes are rapidly and dramatically increased during an immune response. Lymphocytes use specific adhesion molecules and intracellular signaling cascades to migrate and enter secondary lymphoid tissues under resting conditions. It is not clear if the same migration and/or entry pathways are utilized when secondary lymphoid …

Regulatory Mechanisms In Borrelia Burgdorferi-Induced Arthritis, Emily Siebers Hansen

Theses and Dissertations

Lyme arthritis is a common symptom of Lyme borreliosis that involves inflammation of the synovial joints. Elucidating the immune events involved in Lyme arthritis is complicated by the fact that not all individuals infected with B. burgdorferi develop arthritis. Additionally, Lyme arthritis manifests in different severities between affected individuals. It is known that an inflammatory response is initiated by B. burgdorferi infection and that inflammatory T cells contribute to the development of arthritis. However, the anti-inflammatory mechanisms that regulate the pathogenic T cells’ response are not entirely understood. Here, the hypothesis that a dysregulated immune response results in an excessive …

Age-Associated B Cell And T Helper Cell Dysfunction In Rhesus Macaques, Evan Knox Stalvig

Theses and Dissertations

The immune system undergoes drastic changes as we age, known as immunosenescence. An example of this is the dysfunction and subpopulation distribution changes of immune cells. Due to immunosenescence, the elderly have a higher risk of complications and rapid progression of new challenges to the immune system, including human immunodeficiency virus (HIV). In an effort to determine the mechanism of dysfunction of humoral immunity due to age, I compared B cell and T cell responses to non-specific, mitogenic stimuli between aged and young adult rhesus macaque peripheral blood mononuclear cells (PBMCs). Analysis by flow cytometry revealed several differences in B …

Effects Of Drift, Selection And Gene Flow On Immune Genes In Prairie Grouse, Zachary Bateson

Theses and Dissertations

Fragmentation of natural habitats is related to population decline in many species. The resulting small and isolated populations are expected to lose genetic variation at a rapid rate, which reduces the ability to adapt to environmental change. One concern is that small populations are more susceptible to emerging pathogens due to the loss of variation at immune genes. My dissertation examined the relative effects of gene flow, genetic drift and selection on immune genes in prairie-chickens (Tympanuchus cupido), a species that has undergone drastic population declines across their range. In the first chapter, I examined how artificial gene flow through …

Migration Of Myeloid-Derived Suppressor Cells To Tumor And Tumor-Draining Lymph Node In A Murine Model Of Breast Cancer, Vyara Matson

Theses and Dissertations

Myeloid-derived suppressor cells (MDSC) consist of two major subsets, monocytic MDSC (M-MDSC) and polymorphonuclear MDSC (PMN-MDSC), both of which expand in cancer and suppress the activation of naïve T cells in the tumor-draining lymph node (TDLN) and the function of effector T cells in the tumor microenvironment. Thus, the ability of MDSC to enter the TDLN and the tumor is likely to be critical for suppression of the anti-tumor immune response. L-selectin mediates the homing of circulating naïve lymphocytes to lymph nodes and the migration of conventional myeloid cells, such as neutrophils and monocytes, to sites of inflammation, but its …

The Effects Of 830nm Light On Inflammation In Retinitis Pigmentosa, Krystal Marie Bach

Theses and Dissertations

Purpose: Retinitis Pigmentosa (RP) is an inherited retinal degenerative disease and the most common cause of blindness in developed countries, affecting approximately 1 in 4,000 people. RP is characterized by photoreceptor cell death and recent studies suggest that chronic inflammation may play a key role in the pathogenesis of RP. Currently, there are no known treatments or preventive measures to delay or halt the loss of photoreceptor cells. Photobiomodulation (PBM) by light in the far-red or near-infrared (NIR) range of the light spectrum has been documented to help promote cell survival and reduce inflammation in several disease states. Recent studies …

The Mechanism Of Suppression By A Protective Peptide In A Mouse Model Of Multiple Sclerosis, Alaa Mansour Almatrook

Theses and Dissertations

Multiple Sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS). MS is characterized by an immune response directed against myelin sheath. This immune response results in demyelination, which leads to the clinical symptoms of MS. It is accepted that MS is mediated by T helper 1/ T helper 17 immune responses. However, the role of B cells and antibodies (Abs) are still under debate. The primary animal model for MS is the experimental autoimmune encephalomyelitis (EAE) that is induced by immunizing animals with one of the myelin components. We previously showed that immunizing mice with the …

Impaired T Lymphocyte Responses In Older Macaques: Possible Implications For Lentiviral Disease Progression, Sopitsuda Bunnag

Theses and Dissertations

Lentiviral infections of humans and rhesus macaques result in acquired immunodeficiency almost invariably. Yet the duration between the initial infection and the onset of generalized failure of the immune system varies between subjects, in both organisms. Furthermore, acquiring the infection at an older age tends to accelerate disease progression, but mechanisms underlying the latter phenomenon have not been elucidated. It is widely accepted that the events that take place during the very early stages of infection play a critical role in determining disease progression. During this brief period, a fierce competition between viral virulence mechanisms and host immune defenses takes …

Effects Of 670 Nm And 830 Nm Light On The Immune Response To Borrelia Burgdorferi, Felice Chen

Theses and Dissertations

ABSTRACT

EFFECTS OF 670 NM AND 830 NM LIGHT ON THE IMMUNE RESPONSE TO BORRELIA BURGDORFERI

by

Felice Chen

The University of Wisconsin-Milwaukee, 2015

Under the Supervision of Dean T. Nardelli, Ph.D. and Janis T. Eells, Ph.D.

Lyme arthritis is a debilitating joint disorder that arises from Lyme disease, which is a result of infection by the spirochete Borrelia burgdorferi. Antibiotics are the traditional treatment for Lyme disease, but chronic arthritis may persist in some patients despite antibiotic treatment. Therefore, other forms of treatment for Lyme arthritis are needed. Photobiomodulation (PBM) using red or near-infrared light, with wavelengths between 630 …

Impact Of Gestational Exposure To 2,3,7,8-Tetrachlorodibenzo-P-Dioxin On T Lymphocyte Development, Lori S. Ahrenhoerster

Theses and Dissertations

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous environmental contaminant and the best characterized agonist of the arylhydrocarbon receptor (AHR), a transcription factor crucial to the detoxification of numerous xenobiotics. Studies in animals show that TCDD is immunosuppressive in adult exposures, and epidemiological studies have found an association between TCDD exposure and hematologic cancers. Additionally, developmental exposure to TCDD has been shown to increase the likelihood of autoimmunity and to impair immune response to later-life infections. The cells of the immune system are all descended from multipotent hematopoietic stem cells (HSCs) that originate in the fetus. This multipotency, defined as the ability to …

Th17 Cell-Associated Response To Borrelia Burgdorferi Outer Surface Protein A, Megan Elizabeth Johnson

Theses and Dissertations

Arthritis is a common symptom of Lyme disease, a debilitating condition resulting from infection with Borrelia burgdorferi. A protein found on the surface of B. burgdorferi, outer surface protein A (OspA), is known to elicit an inflammatory immune response involving T helper cells. T helper 17 (Th17) cells are associated with the inflammatory cytokines interleukin-17 (IL-17) and interleukin-23 (IL-23) and have been implicated in the development of Lyme arthritis. The objective of this thesis is to provide further characterization of the immune response to B. burgdorferi OspA. The central hypothesis of this thesis is: Vaccination with OspA will predispose mice …

Modulation Of Interleukin-17 By Tumor Necrosis Factor Alpha During The Immune Response To Borrelia Burgdorferi, Velinka Medic

Theses and Dissertations

Arthritis is one of the main complications of late-stage Lyme borreliosis. Cytokines play an important role in the persistent inflammation that is elicited by the causative agent of disease, Borrelia burgdorferi. Tumor necrosis factor alpha (TNF-alpha) is a pro-inflammatory cytokine that is induced by B. burgdorferi and that has been implicated in development of arthritis. However, in a mouse model of Lyme arthritis, treatment with anti-TNF-alpha; antibodies increased the severity of disease. By contrast, injection of recombinant TNF-alpha; ameliorated arthritis in this model. These findings suggested that other factors might be involved during the development of Lyme arthritis. One possible …

Life After Adhesion: L-Selectin Throughout The T Cell Lifespan, Abner Garcia Fernandez

Theses and Dissertations

Lymphocytes require antigenic encounter to activate and proliferate, eventually clearing the source of antigenic challenge. The peripheral lymph nodes (PLN) are the primary sites of antigenic encounter and thus the ability of lymphocytes to migrate to this tissue is a requirement for mounting effective immune responses. The process of lymphocyte migration to the PLN is known as the "adhesion cascade". Specifically, lymphocytes are captured from the blood through the adhesion molecule, L-selectin, followed by CC chemokine receptor 7 (CCR7)-mediated integrin activation, which ultimately results in cell transmigration into the PLN. Because the PLN is the site where antigenic encounter is …

Adhesion Molecule Regulation Of Regulatory T Cell Migration, Jessica Jean Loppnow

Theses and Dissertations

Regulatory T (Treg) cells mediate tumor immune evasion by suppressing anti-tumor effector T cell responses in peripheral lymphoid tissues and within the tumor. While elevated Treg cell numbers have been shown to correlate with increased tumor growth, mechanisms that regulate their distribution within secondary lymphoid tissue and tumor tissue are not well understood. L-selectin, an adhesion molecule constitutively expressed on all classes of leukocytes, functions early in the adhesion cascade and regulates the migration of lymphocytes to lymph nodes through high endothelial venules. In addition, L-selectin can mediate migration of lymphocytes to sites of inflammation by binding to ligands present …

Statistical Investigation Of The Immune Response In Non-Human Primate Models, Annika Laser

Theses and Dissertations

The human immunodeficiency virus (HIV) was first detected more than 30 years ago. Since then, intensive research has been done to develop a broadly protective vaccine, though without success. Our goal is to unveil some features of the protective immunity in non-human primate lentiviral infections in order to emulate HIV-infection. Two primate species have been studied, rhesus macaques (Rh) (Macaca mulatta) and African

green monkeys (Ag) (Chlorocebus spp.). Simian immunodeficiency virus (SIV) infection is non-pathogenic to Ag while Rh develop an AIDS-like illness. In this study, peripheral blood mononuclear cells (PBMC) from 8 Ag and 27 Rh were stimulated with …

Identification Of Immunomodulatory Cells Induced By 670 Nm Light Therapy In An Animal Model Of Multiple Sclerosis, Erin Christine Koester

Theses and Dissertations

Multiple sclerosis is an autoimmune, demyelinating disease characterized by neurodegeneration and inflammation of the central nervous system. It affects approximately 250,000 people in the United States alone, with women being affected two times more than men. Experimental Autoimmune Encephalomyelitis (EAE) is the primary animal model of MS, sharing clinical signs and histopathology with MS. The current paradigm supports MS/EAE induction by myelin reactive CD4+ T cells that cross the blood brain barrier to induce an inflammatory response that leads to the destruction of the myelin sheath and eventual loss of axons. Recent data suggest that axonal loss and disease progression …

Amelioration Of Experimental Autoimmune Encephalomyelitis Using The Myelin Oligodendrocyte Glycoprotein35-85 Peptide, Vrushali Vinay Agashe

Theses and Dissertations

Multiple sclerosis (MS) is a chronic debilitating disease affecting the central nervous system (CNS) in humans. Experimental autoimmune encephalomyelitis (EAE) remains the primary animal model of MS. MS/EAE are considered to be autoimmune diseases mediated by CD4+ T helper (TH) cells. The role of B cells and antibody is under debate. Previous studies established B cell dependent (induced with recombinant myelin oligodendrocyte glycoprotein, [rMOG]) and B cell independent (induced with the MOG35-55 peptide) animal models of EAE. The identification of a unique B cell epitope (MOG amino acids [aa] 46-85) preceding the identified protective epitope (MOG61-85) led to the hypothesis …

Role Of Interleukin-17 In The Adaptive Immune Response In Lyme Arthritis, Emily Siebers

Theses and Dissertations

Lyme arthritis is a devastating symptom of Lyme borreliosis that causes severe inflammation of the synovial joints. Interleukin-17 (IL-17) plays a role in the pathogenesis of various arthritides, including, possibly, Lyme arthritis, by causing the expression of genes involved in the production of inflammatory cytokines by synoviocytes. However, the cellular sources of IL-17 in the context of Borrelia burgdorferi infection are unknown, as are the effects of these cells on the development of arthritis and stimulation of humoral immunity through the production of borreliacidal antibodies. Using multiple models of Lyme arthritis, the hypothesis that IL-17 produced by CD4+ cells contributes …