Medical Immunology Commons^™

Limiting H1n1 Replication Via The Dsrnai Pathway Using Sequence-Specific Ldsrna, Shawn Marie Sharon Carr, Stephanie Dewitte-Orr

Theses and Dissertations (Comprehensive)

The seasonal influenza virus causes a common respiratory illness that can be life threatening to the immunocompromised, the very young, and the elderly. The current strategies for avoiding a serious influenza virus infection are good hygiene practices and the annual influenza vaccine. Unfortunately, last year’s influenza virus vaccine effectiveness ranged between 32-60% for children and adolescents and 46-54% for adults. These low efficacy rates are due to the vaccine often targeting hemagglutinin, a highly variable surface protein. This thesis seeks to create a prophylactic treatment via the RNA interference (RNAi) response that targets the virus’s conserved genes that are integral …

Immune Pathway Modulation In Melanoma Using Chitosan Nanoparticle-Mediated Dsrna Delivery, Bethel C. Iwuji

Theses and Dissertations (Comprehensive)

Cancer is a group of diseases characterized by abnormal and uncontrolled cell division, which typically results in the formation of tumours. Even with advances in treatments, cancer remains one of the leading causes of death globally. Melanoma is an aggressive form of skin cancer which is highly malignant, develops in the pigment-producing cells of the skin, melanocytes, and in the late stages of the disease poses a significant challenge for therapeutic intervention due to its multidrug resistance. The innate immune system is the first line of defence against invading pathogens, including viruses, bacteria, and fungi, and can recognize and destroy …

Administration Of Anti-Gfap Antibodies Increases Cgrp Expression And Increases Pain Hypersensitivity In Spinal Cord Injured Animals, Georgene W Hergenroeder, Samuel T Molina, Juan J Herrera

Faculty, Staff and Student Publications

Background: Spinal cord injury (SCI) results in a multitude of cellular and pathological changes including neuronal loss, axonal damage, gliosis, and loss of motor and sensory function. In 40%-70% of patients, SCI can also trigger the development of neuropathic pain. Our previous study demonstrated that SCI patients who developed autoantibodies to glial fibrillary acidic protein (GFAP) were at increased risk for the subsequent development of neuropathic pain. However, whether GFAP autoantibodies (GFAPab) contribute to the development of neuropathic pain after SCI had yet to be examined.

Objective: Using a mid-thoracic contusion model of SCI in male Sprague-Dawley rats, we examined …

Thromboelastography Versus Thromboelastometry For Unfractionated Heparin Monitoring In Adult Patients On Extracorporeal Membrane Oxygenation, Ellen B Yin, Arthur W Bracey, Subhasis Chatterjee

Faculty, Staff and Students Publications

Background: Monitoring the anticoagulant effect of unfractionated heparin (UFH) in extracorporeal membrane oxygenation (ECMO) patients is complex but critically important to balance the risks of treatment related bleeding and circuit thrombosis. While guidelines recommend using more than one method to monitor UFH activity, the use of thromboelastometry (ROTEM) to monitor UFH in ECMO patients has not been investigated in detail.

Methods: This is an observational, single-center retrospective study looking at adult ECMO patients on UFH that had ROTEM and thromboelastography (TEG) tests obtained concurrently. A total of 20 samples were obtained from nine patients during the study period, …

The Characterization Of Il-27 Production And Its Impact On T Cell Antigen-Specificity And Diversity In A Neonatal Bcg Vaccination Model, Ashley M. Divens

Graduate Theses, Dissertations, and Problem Reports (ETD)

Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb), and it has plagued humans for most of recorded history. Despite strong efforts to prevent and treat TB, it remains the leading cause of death due to a pathogen and is most prevalent in certain regions of Asia and Africa. Currently, the only approved vaccine to prevent TB is the live-attenuated Bacillus Calmette-Guérin (BCG) vaccine. Most countries have a universal BCG vaccination policy, but the vaccine ultimately fails to be protective. The BCG vaccine is most effective in children and protects against disseminated TB, but protection wanes 10-15 years after vaccination causing …

Gout Flare Burden In The United States: A Multiyear Cross-Sectional Survey Study, Jasvinder A Singh, Amy Morlock, Robert Morlock

Faculty, Staff and Students Publications

OBJECTIVE: The objective of this study was to assess the burden of gout flares and examine associated patient characteristics and outcomes in a sample of US adults.

METHODS: Data were collected via an online survey of US adults ≥18 years using a random stratified sampling framework. Participants with gout completed questions about treatments, serum urate (SU) levels, severity, satisfaction with control, and gout flares. All participants completed the Veterans RAND 12-Item Health Survey, the Generalized Anxiety Disorder 7-Item Scale, and the Patient Health Questionnaire 9-Item Scale. Data were summarized using descriptive statistics. Multivariable-adjusted logistic regression analyses examined factors predictive of …

Outcomes With Bridging Radiation Therapy Prior To Chimeric Antigen Receptor T-Cell Therapy In Patients With Aggressive Large B-Cell Lymphomas, Gohar S Manzar, Chelsea C Pinnix, Stephanie O Dudzinski, Kathryn E Marqueen, Elaine E Cha, Lewis F Nasr, Alison K Yoder, Michael K Rooney, Paolo Strati, Sairah Ahmed, Chijioke Nze, Ranjit Nair, Luis E Fayad, Michael Wang, Loretta J Nastoupil, Jason R Westin, Christopher R Flowers, Sattva S Neelapu, Jillian R Gunther, Bouthaina S Dabaja, Susan Y Wu, Penny Q Fang

Faculty, Staff and Student Publications

Background: Select patients with relapsed/refractory aggressive B cell lymphoma may benefit from bridging radiation (bRT) prior to anti-CD19-directed chimeric antigen receptor T cell therapy (CAR-T). Here, we examined patient and treatment factors associated with outcomes and patterns of failure after bRT and CAR-T.

Methods: We retrospectively reviewed adults with diffuse large B-cell lymphoma (DLBCL) who received bRT prior to axicabtagene ciloleucel, tisagenlecleucel, or lisocabtagene maraleucel between 11/2017-4/2023. Clinical/treatment characteristics, response, and toxicity were extracted. Survival was modeled using Kaplan-Meier or Cox regression models for events distributed over time, or binary logistic regression for disease response. Fisher's Exact Test or Mann-Whitney …

Dedifferentiated Liposarcomas Treated With Immune Checkpoint Blockade: The Md Anderson Experience, Madeline B Torres, Cheuk Hong Leung, Marianne Zoghbi, Rossana Lazcano, Davis Ingram, Khalida Wani, Emily Z Keung, M Alejandra Zarzour, Christopher P Scally, Kelly K Hunt, Anthony Conley, Andrew J Bishop, B Ashleigh Guadagnolo, Ahsan Farooqi, Devarati Mitra, Alison K Yoder, Michael S Nakazawa, Dejka Araujo, Andrew Livingston, Ravin Ratan, Shreyaskumar Patel, Vinod Ravi, Alexander J Lazar, Christina L Roland, Neeta Somaiah, Elise F Nassif Haddad

Faculty, Staff and Student Publications

Background: Dedifferentiated liposarcoma (DDLPS) is one of the most common types of soft tissue sarcoma (STS) characterized by liposarcomatous differentiation and a predilection for the retroperitoneum. Despite the growing number of histology-specific immune checkpoint blockade (ICB) trials in STS, it is still difficult to identify the radiographic objective response rate (ORR) for DDLPS in the real world setting. This study aimed to evaluate the ORR and survival of patients with DDLPS treated with ICB at a single center.

Methods: We conducted a retrospective study of 31 patients with pathologically confirmed DDLPS treated with ICB at MD Anderson Cancer Center between …

Characterizing Spatial Immune Architecture In Metastatic Melanoma Using High-Dimensional Multiplex Imaging, Joel Eliason, Santhoshi Krishnan, Yasunari Fukuda, Matias A Bustos, Dan Winkowski, Sungnam Cho, Akshay Basi, Regan Baird, Elizabeth A Grimm, Michael A Davies, Dave S B Hoon, Arvind Rao, Jared K Burks, Suhendan Ekmekcioglu

Faculty, Staff and Student Publications

Introduction: Immune checkpoint inhibitors (ICIs) have significantly improved survival for patients with metastatic melanoma, yet many experienceresistance due to immunosuppressive mechanisms within the tumor immune microenvironment (TIME). Understanding how the spatial architecture of immune and inflammatory components changes across disease stages may reveal novel prognostic biomarkers and therapeutic targets.

Methods: We performed high-dimensional spatial profiling of two melanoma tissue microarrays (TMAs), representing Stage III (n = 157) and Stage IV (n = 248) metastatic tumors. Using imaging mass cytometry (IMC) and multiplex immunofluorescence (mIF), we characterized the phenotypic, functional, and spatial properties of the TIME. Cellular neighborhoods were …

Cord Blood-Derived Ink T Cells As A Platform For Allogeneic Car T Cell Therapy, Maison Grefe, Abel Trujillo-Ocampo, Jelita Clinton, Hong He, Ling Yu, Dan Li, Qing Ma, Elizabeth J Shpall, Jeffrey J Molldrem, Jin S Im

Faculty, Staff and Student Publications

CD1d-restricted invariant Natural Killer (iNK) T cells are a suitable candidate for allogeneic Chimeric Antigen Receptor (CAR) T cell therapy as they do not cause graft-versus-host disease (GvHD) due to the monomorphic nature of CD1d proteins. However, the phenotypic and functional heterogeneity of iNK T cells from adult donors (AD) may lead to the inconstant CAR-iNK T cell products. Cord blood-derived (CB) iNK T cells, in contrast, exhibit inter-donor homogeneity in phenotype including uniform CD4 expression and are enriched in memory iNK T cell populations. Thus, we evaluated the preclinical therapeutic potential of iNK T cells derived from cord blood …

Stat3 Inhibition In Combination With Cd47 Blockade Inhibits Osteosarcoma Lung Metastasis, Pradeep Shrestha, Rejeena Shrestha, You Zhou, Rafal Zielinski, Waldemar Priebe, Eugenie S Kleinerman

Faculty, Staff and Student Publications

Background: New therapies are urgently needed for patients with osteosarcoma (OS). STAT3 and CD47 are potential therapeutic target in OS. Here we investigated the therapeutic activity of the orally bioavailable STAT3 inhibitor, WP1066, and anti-CD47 antibody using OS mouse models.

Methods: Cytotoxic effect of WP1066 against OS cell lines and its immunomodulatory effects were evaluated in vitro. Experimental metastasis and orthotopic syngeneic mouse models were used to investigate the therapeutic efficacy of WP1066 and anti-CD47 antibody. Further flow cytometric analysis was performed.

Results: STAT3 was constitutively activated in multiple human and mouse OS cell lines. WP1066 suppressed STAT3 activation …

The Role Of The Triglyceride-Glucose Index As A Biomarker Of Cardio-Metabolic Syndromes, Verena Gounden, Sridevi Devaraj, Ishwarlal Jialal

Faculty, Staff and Students Publications

BACKGROUND: The Triglyceride-glucose (TyG) index represents a simple, cost-effective, and valid proxy for insulin resistance. This surrogate marker has also been proposed as a predictor of metabolic and cardiovascular disease (CVD). In this descriptive review, we aimed to assess the utility of the TyG index as a predictive biomarker of cardiometabolic diseases.

METHODS: A search was conducted in PubMed, and Web of Science to identify cross-sectional and more importantly prospective studies examining the use of the TyG index as a predictive biomarker. The following terms were utilized in addition to the TyG index: "insulin resistance", "metabolic syndrome", "diabetes"; "cardiovascular diseases". …

Prenatal Identification Of Intracardiac Mass Expedites Surgical Management Of Capillary-Venous Malformation, Derek M Norton, Mounica Y Rao, Jianhong Zhang, M John Hicks, Anitha Parthiban, S Kristen Sexson Tejtel

Faculty, Staff and Students Publications

Fetal and neonatal cardiac tumors are rare and often benign. Clinical presentation is primarily related to mass effect, pericardial effusion or arrhythmia. Prenatal detection can assist with risk assessment and inform optimal delivery plan and postnatal management. We report a fetus with a right atrial mass discovered in the third trimester. After successful surgical resection, pathology confirmed the mass to be a capillary-venous malformation, which are rare and challenging to diagnose. The true incidence of these vascular malformations within cardiac spaces is difficult to discern given the historic classification of numerous different vascular malformations under the umbrella term hemangioma.

5-Fluorouracil Induced Oxidative Stress Is Variable Across Triple Negative Breast Cancer Cell Lines, Rachel L. Walker

Departmental Honors & Graduate Capstone Projects

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with treatment limited to chemotherapy. However, not all patient tumors respond to chemotherapy. The variable cytotoxic effects of chemotherapies may be due to how cancer cells regulate reactive oxygen species (ROS). In this study, we examined two mouse breast cancer cell lines: 4T1 and EO771, vary when treated with hydrogen peroxide (H2O2) and 5-Fluorouracil (5FU), known ROS-inducing substances. In 4T1 cells H2O2 increased oxidized DNA but caused minimal cell death. While in EO771 cells that same amount of H2O2 caused complete apoptosis. Cell number, ROS, and cell death showed …

Early Host Defense Against Virus Infections, Søren R. Paludan, Thomas Pradeu, Andreas Pichlmair, K. Brad Wray, Jacob Giehm Mikkelsen, David Olagnier, Trine H. Mogensen

Presidential Fellows Articles and Research

Early host defense eliminates many viruses before infections are established while clearing others so they remain subclinical or cause only mild disease. The field of immunology has been shaped by broad concepts, including the pattern recognition theory that currently dominates innate immunology. Focusing on early host responses to virus infections, we analyze the literature to build a working hypothesis for the principles that govern the early line of cellular antiviral defense. Aiming to ultimately arrive at a criteria-based theory with strong explanatory power, we propose that both controlling infection and limiting inflammation are key drivers for the early cellular antiviral …

Multicenter Clinical Performance Evaluation Of The Neumodx™ Ct/Ng Assay 2.0, B. Van Der Pol, A. Avery, Stephanie N. Taylor, J. Miller, C. L. Emery, A. English, G. B. Lazenby, Rebecca Lillis, J. Ruth, D. Young, S. Young, S. Chavoustie, L. Crane, V. Reid, G. Wall, S. Johnson

School of Medicine Faculty Publications

Background: Given the continued increases in rates of both Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infection, additional diagnostic assays may be useful in increasing access to testing for these sexually transmitted infections. We evaluated the performance of the NeuMoDx™ CT/NG Assay 2.0 on the NeuMoDx-96 and NeuMoDx-288 Molecular Systems. Methods: The clinical sensitivity and specificity of the assay was assessed when used with: 1) endocervical swabs; 2) self-, and clinician-collected vaginal swabs; and 3) first-catch urine specimens (female and male). Results were compared to a patient infection status based on US Food and Drug Administration (FDA)-cleared assays. Results: The …

Review Of The Diagnosis, Pathophysiology, And Treatment Of Naegleria Fowleri-Induced Primary Amoebic Meningoencephalitis, Terrance Zhang

MCB Articles

Naegleria fowleri is a thermophilic, ubiquitous, free-living amoeba, but is also known as the “brain-eating” amoeba. This is the etiological agent of a rare and fulminant waterborne disease known as Primary Amoebic Meningoencephalitis (PAM) that is acutely fatal in 90-99% of reported cases. Those who come into contact with infested waters are at risk of introducing the amoeba into their upper nasal canal, whence the trophozoite form is known to migrate along the olfactory nerve, through the cribriform plate, and enter the central nervous system. Although the exact pathogenesis of N. fowleri is not known, studies have demonstrated contact-dependent and …

Elucidating The Mechanism Of Interleukin-17a Signaling In The Pathogenesis Of West Nile Virus, Farzana Nazneen

Dissertations

West Nile Virus (WNV), a neurotropic flavivirus transmitted by mosquitoes, is a leading cause of viral encephalitis in the United States and remains a significant public health concern. Unfortunately, no vaccine or therapeutic intervention is available against WNV infection. Previous studies, including ours, demonstrated that interleukin-17A (IL-17A) signaling increases the cytotoxic potential of CD8⁺ T cells to facilitate WNV and parasite clearance; however, the molecular mechanism is not understood. IL-17 receptor C (IL-17RC) is an obligatory co-receptor with IL-17 receptor A (IL-17RA) for signaling induced by IL-17A, IL-17A/F, and IL-17F. In this study, we found that IL-17RC deficient ( …

Determining Evolutionary Conservation Of Mhc-E And Vista Interaction, Julia Glenn

2024 Fall Honors Capstone Projects - Archive

Research in the Weidanz laboratory is focused on cellular molecules which inhibit immune activation, known as immune checkpoints. One example is HLA-E, which can modulate immune responses at homeostasis or in the context of cancer. HLA-E typically acts by presenting short canonical peptides (VL9s) and binding to CD94/NKG2A receptors on NK cells and T cells. The Weidanz laboratory’s research has found that in the absence of these VL9 peptides, HLA-E binds to another immune checkpoint, VISTA, instead of CD94/NKG2A. Therefore, the HLA-E/VISTA interaction is peptide-dependent. The current study aims to determine if this peptide-dependent interaction is evolutionarily conserved using the …

Novel Mouse Models To Study The Role Of T Cells In Cardiac Autoimmunity, Meghna Sur

Dissertations and Doctoral Documents, University of Nebraska-Lincoln, 2023–

Myocarditis patients can chronically develop dilated cardiomyopathy and autoreactive T cells could contribute to the disease pathogenesis, but defining their antigen specificity remains a major challenge. To fill this gap, we generated T cell receptor (TCR) transgenic (Tg) mice specific to cardiac myosin heavy chain (Myhc)-α 334–352 and made a few observations. First, we unexpectedly noted both CD4 and CD8 T cells expressing TCRs specific to Myhc-α 334–352. Second, while Tg T cells from myocarditis-resistant C57BL/6J mice did not respond to Myhc-α 334–352, those from immunized mice responded, indicating that in vivo priming is necessary to break tolerance. Third, upon …