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  • 1. Judge, Chelsey IL-7-MEDIATED CD56BRIGHT NK CELL FUNCTION IS IMPAIRED IN HCV IN PRESENCE AND ABSENCE OF CONTROLLED HIV INFECTION, WHILE CD14BRIGHTCD16- MONOCYTES NEGATIVELY CORRELATE WITH CD4 MEMORY T CELLS AND HCV DECLINE DURING HCV-HIV CO-INFECTION

    Doctor of Philosophy, Case Western Reserve University, 2017, Pathology

    HCV-infection affects approximately 170 million worldwide, with 60-85 percent of acute-infections resulting in chronic-infection, and a significant proportion are co-infected with HIV. HCV-infection causes increased morbidity and mortality in HCV-HIV co-infection. HIV-infection alters HCV-disease pathogenesis, accelerating progression to cirrhosis and liver failure. While HCV-therapy has greatly improved, the cost remains a barrier and is not expected to completely remove HCV from the population. We need a better understanding of the immune-response to HCV to develop successful vaccine strategies. HCV-containment and -clearance is dependent on efforts of the innate and adaptive immune-response. CD4 memory T-cells are critical in viral-clearance, by producing IFN¿ and mediating CD8 T-cell responses. NK cells have been shown to exert an important role in control of HCV-infection by lysis of infected-cells and cytokine release. Monocytes may partly shape this HCV-directed response, via direct-contact with CD4 T-cells and NK cells and in production of soluble factors. IL-7 has been demonstrated to enhance NK cell IFN¿ production, and the IL-7 receptor a chain (CD127) is expressed on NK cells. We measured CD127 expression on NK cell subsets of uninfected donors, chronic HCV-infected treatment-naive, HIV-infected on ART and HCV-HIV co-infected subjects on ART. We demonstrate that CD56bright NK cell CD127 expression negatively correlated with HCV plasma levels in HCV mono-infection and HCV-HIV co-infection. We observed IL-7-induced NK cell activation, cell-cycling, IFN¿ release and cytolytic function, with impairments in HCV- and HIV-infections. These findings offer a role for IL-7-dependent NK cell function in control of chronic viral infections. Within chronic HCV- and HIV-infection, there have been observations of elevated levels of IL-6 and sCD14, produced in part by monocytes, which contribute to immune-activation. We extended these studies to evaluate th (open full item for complete abstract)
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    Committee: Donald Anthony MD, PhD (Advisor); Dave Canaday MD (Committee Chair); Scott Sieg PhD (Committee Member); Daniel Popkin MD, PhD (Committee Member); Clive Hamlin PhD (Committee Member) Subjects: Immunology

  • 2. Cheung, Michael Immune System mModulation in Victims of Intimate Partner Violence

    Master of Science, University of Akron, 2009, Biology

    The immune system is responsible for protecting the body from disease by identifying by destroying pathogenic microorganisms, materials and even dangerous self-cells. This protection is carried out by specialized cells which are found in the bone marrow, circulating blood, thymus, lymph nodes, spleen, as well as other lymphatic tissues. These cells each carry out specific functions and convey different types of protection. Modulation of the balance of either the number or functionality of these immune cells can lead to immune deficiency, susceptibility to disease, or autoimmune disorders such as chronic inflammation. A number of studies have shown that the immune system can be affected by both physical and psychological stresses, such as depression and post-traumatic stress disorder (PTSD). In the present study we examined immune status in women victims of intimate partner violence (IPV). Immune system parameters measured included both immune cell counts as well as functionality of the cells. The results indicated that victims of IPV who suffered from depression and PTSD showed significantly higher baseline activity of natural killer (NK) cells and decreased change in NK cell activity when stimulated with heat shock protein 60 (HSP60). This drop in reactivity to a typical cellular stress signal could put PTSD positive IPV victims at risk for a number of diseases, including cancer development and viral infection. Also, an increased basal activity of NK cells could indicate an autoimmune pathology. These results may lead to a better understanding of the health issues associated with IPV, PTSD, and depression, and will hopefully assist in the development of better and more complete therapies.
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    Committee: James Holda PhD (Advisor) Subjects: Biology; Health; Immunology; Psychobiology; Womens Studies

  • 3. Ahad, Leena The Immunotherapeutic Approach to Glioblastoma Multiforme

    MS, University of Cincinnati, 2024, Medicine: Cancer and Cell Biology

    Glioblastoma multiforme poses significant treatment challenges, attributed to its distinctive characteristics and immune evasion mechanisms, and carries a grim prognosis despite advancements in therapy. Therefore, rigorous efforts are necessary to uncover additional therapies or other unconventional strategies. Recently, immunotherapies have gained significant traction due to their success in certain malignancies. Immunotherapies use the host's immune system to enhance the ability to combat cancer. These therapies have been in development for over 100 years, and many of them are currently under investigation for treating Glioblastoma multiforme in preclinical and clinical studies. Immunotherapies include antibody therapies, including immune checkpoint blockade, adoptive T cell therapies, cytokine therapies, cancer vaccines, and oncolytic viruses. A deeper understanding of the origins of immunotherapy, immune system dynamics in response to cancer, immune evasion mechanisms of glioblastoma, and the various immunotherapeutic strategies may facilitate the development of novel and effective treatment strategies for glioblastoma. Here, we review the different immunotherapeutic approaches and propose possible combinatory strategies.
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    Committee: Qing Lu Ph.D. (Committee Chair); David Plas Ph.D. (Committee Member); Biplab DasGupta Ph.D. (Committee Member); David Haslam M.D. (Committee Member) Subjects: Oncology

  • 4. Jones, Devin Regulation of cytotoxic programming in CD4+ T cells by Ikaros Zinc Finger Family transcription factors

    Doctor of Philosophy, The Ohio State University, 2023, Biomedical Sciences

    CD4+ T cells are a subset of the adaptive immune response that are classically defined as “helper” type cells, responsible for aiding in the effective recruitment and function of other immune cells. In addition to these traditional helper type roles, however, an additional subset of CD4+ T cells characterized by the ability to perform cytotoxic functions classically attributed to Nature Killer (NK) and CD8+ T cells, has emerged. This additional subset, deemed CD4+ cytotoxic T lymphocytes (CD4-CTLs), produce cytolytic effector molecules and directly kill compromised cells in a major histocompatibility complex class-II (MHC-II) restricted fashion. While initially thought to be a bi-product of in vitro culturing, CD4-CTLs have now been identified in a broad range of both human and murine immune responses. Specifically, CD4-CTLs have been shown to play largely protective roles in numerous antitumor and antiviral responses, including those to influenza and SARS-CoV-2. Conversely, dysregulated CD4-CTLs have been implicated in the pathogenesis of autoimmune diseases, including multiple sclerosis and ulcerative colitis. Despite their documented importance in a wide range of immunological contexts, the mechanisms that underly their differentiation and function remain enigmatic. Here, we first identify the Ikaros Zinc Finger transcription factor Aiolos (encodedby Ikzf3) as a reciprocal regulator of CD4-CTL and T-follicular helper (TFH) cell populations. TFH cells represent a classical CD4+ T helper cell populations that, upon activation and subset specific differentiation, interact with and provide aid to B-cells in the production of high-affinity neutralizing antibodies. In this work, we utilized a murine model of influenza infection, an immunologic context in which both TFH and CD4-CTLs have been shown to play important protective roles. We find that the absence of Aiolos resulted in global disruptions in TFH cell programming, including decreases in key transcription fa (open full item for complete abstract)
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    Committee: Ken Oestreich (Advisor); Hazem Ghoneim (Committee Chair); Thomas Mace (Committee Member); Murugesan Rajaram (Committee Member); Purnima Dubey (Committee Member) Subjects: Biomedical Research; Immunology

  • 5. Krishnamurthy, Animeshasavithri Gene Targeting of Immunosuppressive Proteins in Metastatic Cancer

    Master of Sciences (Engineering), Case Western Reserve University, 2022, Biomedical Engineering

    The knockdown of immune checkpoint proteins, such as VISTA, can allow for the reversal of an immunosuppressed tumor microenvironment back to a pro-inflammatory and immuno-active state, causing inhibition of T-cell suppression and activation of innate myeloid antigen presenting cells. Here, we evaluated whether a folate-targeted nanoparticle could enhance VISTA siRNA delivery, leading to robust reprogramming and activation of an anti-tumor immune response. Flow cytometry studies have indicated that cells of multiple murine triple negative breast cancer and melanoma models that express VISTA also express Folate Receptor β (FRβ), indicating that FRβ targeting of a lipid nanoparticle (LNP) can potentially allow for enhanced uptake of the LNP by immune cells. Uptake of the targeted nanoparticle by the tumor and resulting expansion of activated immune populations, coupled with decreased systemic effects, indicate that IT administration of a FRβ targeted nanoparticle in a murine melanoma model can facilitate effective reprogramming of the tumor immune landscape.
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    Committee: Efstathios Karathanasis PhD (Advisor); Horst von Recum PhD (Committee Member); Vijay Krishna PhD (Committee Member); Steven Eppell PhD (Committee Member) Subjects: Biomedical Engineering

  • 6. Csoltko, Kelly Combined Dermatology-Rheumatology Clinic

    DNP, Kent State University, 2022, College of Nursing

    Psoriasis (PsO), psoriatic arthritis (PsA), dermatomyositis, systemic erythematous lupus (SLE), discoid lupus erythematosus (DLE) are chronic inflammatory autoimmune disorders with overlapping systemic and cutaneous symptoms. Often times there are long intervals between appointments due to availability of the provider and long-distance travel for the veteran to receive care at Veterans Affairs Northeast Ohio Health Care System (VANEOHS), also known as, and may be referred throughout this paper as the Cleveland VA. This causes a delay in implementing or changing treatments for several weeks because these conditions are managed separately between dermatology and rheumatology specialties. Changes continually take place throughout the VA system nationally to improve the way care is provided to the veterans. Changing the way specialty care is delivered to veterans within the VANEOHS is important to influence veterans in a positive manner to want to continue to choose the Cleveland VA to receive their care. Currently there are no combined specialty clinics within the Cleveland VA. This is the first combined dermatology-rheumatology clinic improvement project within VANEOHS that offers an innovative way to deliver specialty care to veterans. The clinic took place once a month and after each veteran's appointment, they were provided with a 17 question Likert-scale survey over a 6- month period. The survey asked questions about their personal experience regarding the way they received care in the past, their understanding about their medical condition, how they would prefer to see their providers in the future, and if there was a personal cost savings. There was no prior questionnaire for comparison; although the positive patient satisfaction regarding patient access and satisfaction of care supports the sustainability of the combined dermatology-rheumatology clinic in the way specialty care is delivered to Veterans at the Cleveland VA medical center.
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    Committee: Dr. Lynn Gaddis (Committee Chair); Dr. Elma Baron (Other); Dr. Pamela Stephenson (Committee Member); Dr. Tracey Motter (Committee Member) Subjects: Nursing

  • 7. Jackson, Courtney Chorioamnionitis induces systemic and mucosal immune responses in the developing fetus

    PhD, University of Cincinnati, 2020, Medicine: Immunology

    A complication that can occur during pregnancy is placenta inflammation, referred to as chorioamnionitis (chorio). Exposure to this inflammatory condition has been associated with several post-natal morbidities. Chorio, particularly severe chorio leads to the increased production of various inflammatory mediators in the amniotic fluid. This inflamed amniotic fluid encounters the fetus, resulting in systemic and mucosal immune responses. However, a full understanding of the fetal responses to the inflammatory milieu created by chorio and the contribution of inflammatory cytokines like IL-1 and TNFa to these responses remains limited. The work presented here examined and characterized the fetal systemic and mucosal immune response to chorio exposure in humans and in a non-human primate (NHP) animal model. Our NHP model in which using intra-amniotic (IA) LPS in the Rhesus macaque, phenocopies severe chorio and allowed us to evaluate the impact of chorio exposure on the fetus. Systemically we found that IA LPS leads to a decreased frequency of CD4+FoxP3+ regulatory T cells (Tregs). However, while CD4+FoxP3+ Tregs are reduced in the context of chorio, they markedly upregulate production of IL-17, becoming the most significant source of this cytokine in inflammatory conditions. A similar, but milder phenotype was found in the cord blood as well. We later found that the Th17-like response was partially controlled by IL-1 or TNFa signaling, but the frequency of CD4+FoxP3+ did not recover after blockade IL-1 or TNF. The presence of a chorio induced Th17-like signature was also found in human cord blood of severe chorio exposed fetuses with sustained elevation of RORC and RORC/FOXP3 mRNA ratio. These findings point to a regulatory/inflammatory disbalance in the fetal systemic response to chorio exposure that particularly impacts regulatory T cells. In our NHP Rhesus macaque model, we also conducted an in-depth analysis of the chorio-induced fetal mucosal immune response in (open full item for complete abstract)
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    Committee: Claire Chougnet Ph.D. (Committee Chair); David Hildeman Ph.D. (Committee Member); Edith Janssen Ph.D. (Committee Member); Alan Jobe M.D. (Committee Member); Ian Lewkowich Ph.D. (Committee Member) Subjects: Immunology

  • 8. Alalade, Emmanuel Intrusion Detection System in Smart Home Network Using Artificial Immune System and Extreme Learning Machine

    MS, University of Cincinnati, 2020, Education, Criminal Justice, and Human Services: Information Technology

    Internet of things (IoT) applications in our daily lives has made life easier, but also comes with associated security threats. The vulnerability of the IoT system stems from the vulnerability of each connected device and transmission of threats through an interconnected home network. Smart homes are one of the applications of IoT, which is comprised of connected devices for easier interaction. An isolated IoT system with no internet connection has some level of safety from attacks because it is not exposed to the internet, although these devices have their innate vulnerabilities from the manufacturer. IoT gateways connecting IoT devices to the internet can create a backdoor into the smart home system that an attacker can exploit. Therefore, Internet-connected IoT devices have a high-security risk and one of the ways to detect an intrusion into an IoT gateway is through anomalies in the traffic passing through it. This thesis introduces early work on an intrusion detection system (IDS) by detecting anomalies in the smart home network using Extreme Learning Machine and Artificial Immune System (AIS-ELM). AIS uses the Clonal Algorithm for the optimization of the input parameters, and ELM analyzes the input parameter for better convergence in detecting anomalous activity. The larger implications of this work are the potential to apply this approach to a smart home network gateway and combine it with a push notification system that will allow the homeowner to identify any abnormalities in the smart home network and take appropriate action to mitigate threats.
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    Committee: Nelly Elsayed Ph.D. (Committee Chair); Jess Kropczynski Ph.D. (Committee Chair); Shane Halse Ph.D. (Committee Member) Subjects: Information Technology

  • 9. Moledina, Muhammed Saad Role of Bb-elicited IL-10 in Suppression of Innate Immune Responses within Murine Skin Tissue

    Doctor of Philosophy (PhD), University of Toledo, 2019, Biomedical Sciences (Medical Microbiology and Immunology)

    Borrelia burgdorferi (Bb) is an extracellular spirochetal bacterium and the causative agent of Lyme disease (LD). In vitro, Bb induces robust immune responses which suggests that Bb could be effectively cleared. However, neither innate nor adaptive immune responses are able to eliminate Bb in vivo resulting in persistent infection. Hence, there is a dysregulation of the immune response occurring in vivo, which cannot be recapitulated in an in vitro system due to the intricacy and complexity of the host tissue milieu. In this study, we utilized intravital microscopy (IVM) along with several transgenic mouse lines, to delineate and identify the immune dysregulation occurring within skin tissues in vivo, which permits this extracellular pathogen to maintain a persistent infection. Our IVM studies identified that Bb undergo a massive proliferation between days 2 to 7 post-infection and peak bacterial numbers are achieved in skin tissues adjacent to the infection site around day 8 post-infection. During this period of acute infection, an activated innate response should be identifying and clearing this extracelluar pathogen, since Bb possess potent agonists. However, host innate responses fail to control the spirochete and Bb numbers undergo almost a 50-fold increase during this period. iv Attainment of peak bacterial numbers is followed by a significant decrease in Bb numbers until day 14 post-infection; subsequently, this low level is maintained for over 2 years. Based on this in vivo persistence data, the two major goals of our study were to 1) delineate whether adaptive immune responses were responsible for the significant decrease in Bb numbers after day 8 post-infection, and 2) determine whether Bb-elicited IL-10 is involved in the dysregulation of innate responses necessary to control Bb numbers during early infection. To test the contribution of the host adaptive responses in reducing Bb numbers, we used several transgenic mice with B cell- and T cell-defi (open full item for complete abstract)
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    Committee: R. Mark Wooten (Committee Chair); Andrea Kalinoski (Committee Member); Kevin Pan (Committee Member); Randall Worth (Committee Member); Robert Blumenthal (Committee Member) Subjects: Biomedical Research; Immunology; Microbiology

  • 10. Pillai, Mahesh Deciphering the Link Between Polychlorinated Biphenyls, Immune Function and Exercise

    Doctor of Philosophy (Ph.D.), Bowling Green State University, 2017, Biological Sciences

    Polychlorinated biphenyls (PCBs) are environmental pollutants and endocrine disruptors, harmfully affecting reproductive, endocrine, neurological and immunological systems. This has implications for processes such as wound healing, which is modulated by the immunological response of the body. Conversely, while PCBs can be linked to diminished wound healing, outside of PCB pollution systems, exercise has been shown to accelerate wound healing. However, the potential for moderate intensity exercise to modulate or offset the harmful effects of a toxin like PCB are yet unknown. Exploration of this possible moderation on local immune response was achieved by measuring wound size and analyzing the concentrations of proinflammatory cytokines, interleukin-1ß (IL-1ß), interleukin-6 (IL-6), keratinocyte chemoattractant (KC), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-a (TNF-a) in wounds (inflicted by punch biopsy) in mice that were not exercised as compared with those previously exercised at moderate intensity by running on a treadmill for 30min/day and then injected intraperitoneally with Aroclor 1254 (industrial mixture of PCB congeners) in doses of either 0, 100, 500 and 1000 ppm (wt/wt of mice). Mice were euthanized at Day 3 or Day 5 (n = 3-6) and skin excised from the wound area was homogenized and analyzed for cytokine content. Systemic effects of exercise on immune function in PCB exposed animals were examined by lipopolysaccharide (LPS) challenge (intraperitoneal injections) and analyzed by measuring the average body temperatures using a thermal imaging camera. Wound healing data revealed that in animals not exercised only the greatest dose of PCB (1000 µg/g) showed a pattern for faster wound healing. Exercise produced a pattern of more rapid wound healing rates compared to the animals administerd similar doses, except for animals administered 100 µg/g PCB. Concentrations of pro-inflammatory cytokines revealed patterns t (open full item for complete abstract)
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    Committee: Lee Meserve Dr. (Advisor); Howard Cromwell Dr. (Other); Todd Keylock Dr. (Committee Member); Scott Rogers Dr. (Committee Member); Vipaporn Phuntumart Dr. (Committee Member) Subjects: Immunology; Kinesiology; Molecular Biology; Physiology; Toxicology

  • 11. Lazarus, John A Role for Interleukin-10 in the Murine Model of Lyme Disease

    Doctor of Philosophy in Medical Sciences (Ph.D.), University of Toledo, 2007, College of Graduate Studies

    Lyme disease is caused by persistent infection with the bacterium Borrelia burgdorferi (Bb) and includes a multisystem disease characterized by periodic inflammation. As it is an obligate parasite, Bb has evolved various strategies to persist for extended times within mammalian and tick hosts. It is largely unknown which immune mediators are important for controlling this spirochete. We have discovered that Interleukin-10- deficient (IL-10-/-) mice exhibit up to 10-fold greater clearance of Bb from target tissues compared to wild type mice, establishing IL-10 as the only cytokine currently known to have such a significant effect on spirochetal clearance. The goals of this work were to identify murine defense mechanisms dysregulated by IL-10 and describe specific effects on Bb clearance. Although increases in Bb-specific antibody by two weeks post infection were noted in IL-10-/- mice compared to wild type controls, these antibodies were not solely responsible for enhanced clearance of Bb. Instead, we demonstrate enhanced innate immune responses in IL-10-/- mice as being important to increased clearance of this spirochete. Upregulation of IL-10 transcript levels in skin harvested early during Bb infection also suggested this cytokine suppression could occur in vivo. We developed a novel in vitro co-culture system to assess Bb-macrophage interactions, which allowed us to show that Bb can elicit rapid and substantial IL-10 production by macrophages, which are significant in that they are resident in skin tissues and direct inflammatory responses. Finally, we illustrate that IL-10 produced by macrophages can act in an autocrine loop to suppress subsequent inflammatory responses that are necessary to promote efficient immune clearance of Bb. These studies have laid the ground work to allow delineation of 169 the host cell types that produce and/or respond to Bb-elicited IL-10, which can hopefully lead to curative treatments of Lyme disease.
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    Committee: R. Mark Wooten (Advisor) Subjects:

  • 12. Vasudevan, Swetha Immune Based Event-Incident Model for Intrusion Detection Systems: A Nature Inspired Approach to Secure Computing

    MS, Kent State University, 2007, College of Arts and Sciences / Department of Computer Science

    Immune System is essential for the survival of the species. How exactly this sophisticated defense mechanism accomplishes the level of discrimination remains deeply enigmatic. Both Immune System and Intrusion Detection System work toward a comparable goal, identifying and responding to malicious agents. The effectiveness of an Intrusion Detection System however, depends on its ability to accurately differentiate between an event and an incident. Today computer scientists and researchers are borrowing some of the underlying principles of Immunology to implement such a system. The Human Immune System primarily involves highly specific recognition of foreign antigens and tolerance of self antigens. For more than six decades, the concept of ‘self / non-self' formed the central theme of Immunology. The model states that all foreign entities that are not part of the organism trigger an immune response, whereas self elements do not. In the last few years, several researchers have challenged the authenticity of this concept and have come up with rival ideas. One such notion is the Danger Theory for Immunology. According to this new viewpoint, the Immune System does not discriminate between self and non-self elements but between danger and non-danger. Danger is perceived as a signal emitted by the cells that die an unnatural death. Detection of a foreign entity occurs in conjunction with the detection of danger signals which are emanated as a result of discontinuity in the constant interactions between the immune receptors and their targets. In this thesis, the author proposes a new Danger Theory based Event-Incident Model for Intrusion Detection System. The proposed model also borrows some key characteristics of autonomous multi-agent system. It employs a group of detectors known as the ‘Mobile Intrusion Detection Squad' and utilizes the ‘Divide and Conquer Approach' to identify and respond to both distributed and coordinated attacks. The literature of Immune-based Intrusio (open full item for complete abstract)
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    Committee: Michael Rothstein (Advisor) Subjects: Computer Science

  • 13. Volovetz, Josephine Sex Bias in the Immune Response in a Murine Glioblastoma Resection Model

    Doctor of Philosophy, Case Western Reserve University, 2024, Molecular Medicine

    Glioblastoma (GBM) is the most common primary malignant brain tumor with a median survival of 15-20 months, despite standard of care treatment: maximally safe resection, radiation, and chemotherapy. The incidence of GBM is 1.6 times higher in males and their survival can be up to 10 months shorter. Females are more responsive to treatment, but the mechanism behind these differences is unclear. The immune system is suppressed in GBM, and there are sex differences in the immune response. While preclinical GBM models are used to interrogate pathophysiology, few of these models include surgery, despite its pivotal role in the standard of care. For my thesis, I developed a preclinical GBM resection model to evaluate whether there is a sex bias in survival and interrogate post-operative, sex-specific immune changes. I found that mice implanted with syngeneic GBM demonstrate a sex bias after resection, with females surviving longer. Bulk RNA sequencing of tumors from mice who underwent either resection, sham surgery, or no surgery revealed no significant differences between male and female resection cohorts, indicating that the main driver underlying these survival differences is likely to not be intrinsic to the tumor. Gene ontology analysis revealed a stronger immune signature in differences found between female resection versus sham surgery groups compared to males. To evaluate the role of the immune system, I repeated survival experiments in NSG mice and found the sex bias was abrogated. Using flow cytometry, I found that female mice who underwent resection had higher levels of immune cell infiltration in the tumor microenvironment compared to sham surgery controls, while resected males had lower levels. Male mice who underwent resection had lower levels of regulatory T cells (Tregs) than their sham surgery counterparts. When survival studies were repeated in Foxp3DTR mice with Treg depletion, the survival sex bias was abrogated, indicating a protective role for Tregs (open full item for complete abstract)
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    Committee: Justin Lathia (Advisor); Jacob Scott (Committee Chair); Matthew Grabowski (Committee Member); Shideng Bao (Committee Member); Jessica Williams (Committee Member) Subjects: Oncology

  • 14. Holmes, Robert Humoral and cellular aspects of the normal and immune response to glycerol teichoid acid in the rabbit /

    Master of Science, The Ohio State University, 1971, Graduate School

    Committee: Not Provided (Other) Subjects:

  • 15. Moon, Taylor Engineering Multi-Action Lipid Nanoparticle Platforms for Cancer Immunotherapy

    Doctor of Philosophy, Case Western Reserve University, 2024, Biomedical Engineering

    Cancer therapy has significantly advanced over the past few decades due to development of improved surgical technique, early detection, and novel therapy development. However, cancer remains one of the most lethal diseases due to metastasis, drug resistance, and recurrence. Immunotherapy holds the promise of utilizing the body's immune system to eliminate cancer cells. Immune checkpoint blockade therapy remains the most common utilization of immunotherapy in the clinical but yields varying degrees of success due to the massively immunosuppressed tumor microenvironment. Discovery of novel immune checkpoints and technology for targeting these checkpoints is critical for the advancement of cancer immunotherapy. The novel immune checkpoint protein VISTA (V-domain Immunoglobulin Suppressor of T cell Activation) impairs the toll-like receptor (TLR)-mediated activation of myeloid antigen presenting cells, promoting the expansion of myeloid derived suppressor cells, and suppressing tumor-reactive cytotoxic T cell function. Gene therapy targeting the VISTA checkpoint protein in conjunction with potent TLR agonists represents a safer yet potent alternative to antibody mediated cancer immunotherapy that has shown toxicity in the clinic. The overall objective of the work in this dissertation is to develop nanoparticle platforms for delivery of gene therapy mediate immune checkpoint blockade cancer immunotherapy regiments. First, a dual action lipid nanoparticle (Dual-LNP) that incorporates a VISTA-specific siRNA and a TLR9 agonist (unmethylated CPG) is developed. The Dual-LNP ensures co-delivery of both cargoes to tumor-infiltrating myeloid cells, leading to simultaneous silencing of VISTA and stimulation of TLR9. Next, the efficacy of the Dual-LNP was tested in multiple solid tumor models. The Dual-LNP treatment achieved a high cure rate in colon carcinoma MC38, melanoma B16F10, and YUMM1.7 models (83%, 60%, and 48%, respectively). Finally, investigation into the immune landsc (open full item for complete abstract)
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    Committee: Efstathios Karathanasis (Advisor); James Basilion (Committee Chair); Li Lily Wang (Committee Member); Andrew Shoffstall (Committee Member); William Schiemann (Committee Member) Subjects: Biomedical Engineering; Nanotechnology

  • 16. Islam, Md Aminul Investigating the role of innate B cell and SLAMF9 receptor in Acinetobacter baumannii respiratory infection using a mouse pneumonia model

    Doctor of Philosophy, Miami University, 2024, Microbiology

    Acinetobacter baumannii is a Gram-negative opportunistic pathogen commonly associated with severe nosocomial infections such as pneumonia, urinary tract infections, wound infections, and meningitis in immunocompromised individuals. This bacterium poses a serious global health threat due to its intrinsic and acquired resistance to currently available antibiotics, resulting in a high mortality rate. Given that the treatment options are limited, a comprehensive understanding of host immune responses is essential to develop alternative therapeutics against this human pathogen. Because we aim to better understand host immune responses, with a long-term goal of developing novel immunotherapeutics, our study has focused on determining the functions of innate B cells and the signaling lymphocyte activation molecule family member 9 (SLAMF9) receptor during A. baumannii infection. The work presented in this dissertation shows that B cell-deficient mice are highly susceptible to A. baumannii respiratory infection. Our work also demonstrates that passive transfer of natural antibodies (NAbs) can rescue mice from severe infection, and that NAbs exert this protective function through complement-mediated opsonophagocytosis of A. baumannii. RNA sequencing and flow cytometric analyses of mouse lung tissues reveal that B cells are crucial for regulating pulmonary recruitment of multiple innate immune cells, including eosinophils and natural killer cells, following A. baumannii infection. They are also important for preventing extrapulmonary dissemination of A. baumannii at early stages of infection. In this study, we also examined the role of SLAMF9, a poorly characterized leukocyte receptor, using an intranasally infected mouse pneumonia model. The SLAMF9-deficient (Slamf9-/-) mice exhibit enhanced clearance of A. baumannii from the lung, liver, and spleen at 24 hours post-infection. Transcriptomic analysis of whole lung tissue shows significantly higher expression of several interf (open full item for complete abstract)
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    Committee: Timothy Wilson, PhD (Advisor); Luis Actis, PhD (Advisor); Paul James, PhD (Committee Member); Joseph Carlin, PhD (Committee Member); Mitchell Balish, PhD (Committee Member) Subjects: Microbiology

  • 17. Engelhart, Morgan Unraveling the Molecular Mechanisms of Microbiota Induced Immune Tolerance

    Doctor of Philosophy, Case Western Reserve University, 2024, Molecular Medicine

    Homeostasis between the gut microbiome and the intestinal immune system is essential to human health and is maintained via anti-inflammatory pathways that promote immune tolerance against the gut microbiome. Microbiota mediated induction of these pathways is essential, however the mechanisms by which they function remain poorly defined. Throughout this thesis we use the common gut commensal Bacteroides thetaiotaomicron as a model to interrogate the mechanisms by which it induces anti-inflammatory immune responses. In Chapter 1, we found that B. theta produces a secreted factor capable of inducing the anti-inflammatory cytokine IL-10 in a Toll-like receptor 2 (TLR2)-dependent manner. We identified a B. theta genetic locus that encodes the NQR complex, a member of the electron transport chain, that is required for B. theta to induce IL-10 and found that disruption of the NQR complex altered outer membrane vesicle (OMV) biogenesis, thus decreasing the number of OMVs and hindered IL-10 induction. In Chapter 2, we investigated the immunomodulatory factor(s) B. theta secretes and found that it activates both TLR2/1 and TLR2/6 heterodimers, and that protein precipitation led to diminished IL-10 induction and TLR2 activation. TLR2 recognizes lipid moieties bound to proteins or carbohydrates, therefore we hypothesized that B. theta produces a lipid bound to a protein that is required for this process. We further identified a predicted lipoprotein encoded by gene BT1549 that is required for this process. Finally, in Chapter 3, we investigated whether distinct human isolates of B. theta vary in their ability to induce intestinal regulatory T cells (Tregs). We found that genetically distinct strains stratified into those that induce Tregs and those that do not. Additionally, we found that expression of type-1 IFN-signaling genes were upregulated in the colon of mice colonized with a Treg inducer and hypothesize that B. theta is using t (open full item for complete abstract)
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    Committee: Philip Ahern (Advisor) Subjects: Immunology; Microbiology

  • 18. Grabarz, Theodore The Use of a Habitat Quality Stress Index to Evaluate Stress as an Analog for Proximate Fitness in the American Crow Within a Matrix of Landcover Characteristics to Assess Its Potential Contribution to Disease Etiologies

    Ph.D., Antioch University, 2023, Antioch New England: Environmental Studies

    All organisms occur within spatial and temporal environments to maximize proximate fitness (health) and thus life history outcomes. Previous work has examined the temporal and behavioral aspects of proximate fitness on life history outcomes particularly regarding highly perturbed environments (i.e., climate and land use change, resource extraction, agricultural erosion, etc.). My work focuses on the less examined spatial aspect of these perturbed environments. More specifically, this dissertation examines habitat selection and quality as the basis for understanding stress response (negative and positive feedback mechanisms) to environmental stressors within the larger context of regional or gamma (ɣ) biodiversity. Through the lens of environmental endocrinology, I examine patterns of glucocorticoid (GC) hormone differentiation spatially. I do this to understand how biotic and anthropogenic environmental stressors affect stress response in the American Crow (AMCR). This stress response could have an impact on human disease origins. I examined 13 sites throughout the State of Connecticut between 2019 and 2021, from very rural to very urbanized. I collected 153 opportunistic fecal samples of AMCR, then used radio immunoassay to characterize and quantify the samples as GC hormones, a key chemical constituent that reflects stress response in avian subjects. I then used a geographic information system (GIS) to plot various catchments for each sample centroid as notional representations of AMCR territories. I then overlayed 15 landcover types as biotic and anthropogenic environmental stressors (ESs). I used ordinary least squares linear regression for my initial analyses to evaluate the degree of validity of the ES–GC relationship at discrete locations where samples were taken and subsequently within varying sized territorial catchments. Finally, I reinterpreted a single constrained gravity model for the development of a habitat quality stress index (HQSI) to understand mo (open full item for complete abstract)
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    Committee: James Jordan PhD (Committee Chair); Lisabeth Willey PhD (Committee Member); Antonios Pappantoniou PhD (Committee Member) Subjects: Biology; Conservation; Ecology; Endocrinology; Environmental Studies; Epidemiology; Immunology; Wildlife Conservation

  • 19. Seicol, Benjamin Innate Immune and Complement Activation in the Cochlea and Cochlear Nucleus during Age-related and Noise-induced Hearing Loss

    Doctor of Philosophy, The Ohio State University, 2023, Neuroscience Graduate Studies Program

    Sensorineural hearing loss (SNHL) is a common hearing health disorder caused by damage to cochlear sensory hair cells and neurons, which can occur during normal aging and from acoustic insults throughout the lifespan. Age-related hearing loss (ARHL) describes the form of SNHL that happens in aging patients with progressive loss of hearing perception. Noise-induced hearing loss (NIHL) occurs from noise damage and can happen at any age. Both ARHL and NIHL share similar features in cochlear tissue damages, including the loss of sensory hair cells, auditory neurons, and synapses in the cochlea. Further synaptopathy occurs in the cochlear nucleus (CN), which is where all arriving auditory information from the ear first enters the central nervous system. Acute and chronic cochlear inflammation are associated with worsening outcomes in SNHL. Resident innate immune cells modulate local inflammatory responses and are implicated in both the cochlea and the brain during SNHL. Tissue damage and age-related degeneration increase the activation of both cochlear macrophages and microglia in the brain. These activated immune cells release factors that recruit additional immune cells and alter tissues in ways that can contribute to the progression of pathology. Example signals potentially released by resident immune cells include complement factors, which are proteins also found in circulation that can accumulate in damaged or diseased tissues. This dissertation investigates the activation of innate immune cells, including cochlear macrophages and microglia during ARHL and NIHL, and whether the activation of complement pathways in the cochlea and CN may contribute to SNHL pathophysiology. CBA/CaJ mice were used as the animal model in this research, which were either aged in ambient noise environments to develop ARHL or exposed to various intensities of noise to cause NIHL. Hearing was assessed in all mice and tissues were collected to measure changes in the resident immune cells and (open full item for complete abstract)
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    Committee: Ruili Xie (Advisor); Eric Bielefeld (Committee Member); Ruth Barrientos (Committee Member); Dana McTigue (Committee Member) Subjects: Neurobiology; Neurosciences

  • 20. González-Orozco, Brianda Daniela Kefir Microorganisms: A Treasure Trove for Health-Driven Product Development

    Doctor of Philosophy, The Ohio State University, 2023, Food Science and Technology

    Kefir is a fermented dairy beverage with origin in the Caucasus mountains that has been consumed for centuries due to its attributed health benefits, primarily owed to its diverse microbiota and their valuable metabolites. Kefir has been referred to as one of the “9 food trends to watch for in 2021” by the Institute of Food Technologist and consumers are incorporating kefir-products into their diets as a potential probiotic product. However, consumption of traditional or commercial kefir as a probiotic product presents several drawbacks. Traditional kefir is produced by the fermentation of milk with kefir grains as starter culture, a complex microbial community of bacteria and yeast embedded in an exopolysaccharide matrix. However, according to some reports traditional kefir has limited acceptance among western consumers and due to the complexity of its microbiota and production practices, achieving industrial-level production faces several challenges. Furthermore, in the United States, there is no established standard for commercial kefir products. The United States Food and Drug Administration (FDA) considers microorganisms added to products as dietary supplements, and according to the FDA Code of Federal Regulations Title 21, kefir is categorized as a cultured milk that contains aroma and flavor producing microbial cultures. Therefore, under the present regulation, kefir producing companies have the freedom to incorporate microorganisms without undergoing verification or regulation. As a result, kefir-products on the market are fermented milk products containing different combinations of starter cultures and probiotic strains, varying from one company to the other. Additionally, recent reports indicate that these products do not contain any of the core kefir microorganisms present in traditional kefir and there is lack of research to support their health effects. Given the limitation of traditional kefir and current commercial kefir-products, it is imperative to (open full item for complete abstract)
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    Committee: Valente B. Alvarez (Advisor); Christopher Simons (Committee Member); Ahmed Yousef (Committee Member); Rafael Jimenez Flores (Committee Member) Subjects: Food Science; Microbiology
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