Medical Immunology Commons^™

Magnesium Increases Numbers Of Foxp3+ Treg Cells And Reduces Arthritis Severity And Joint Damage In An Il-10-Dependent Manner Mediated By The Intestinal Microbiome, Teresina Laragione, Carolyn Harris, Nasim Azizgolshani, Christine Beeton, Gerold Bongers, Percio S Gulko

Faculty, Staff and Students Publications

BACKGROUND: Rheumatoid arthritis (RA) is a common autoimmune disease with emerging environmental and microbiome risk factors. The western diet is typically deficient in magnesium (Mg), and there is some evidence suggesting that Mg may have anti-inflammatory properties. But the actual role of Mg supplementation in arthritis or in T cell subsets has not been explored.

METHODS: We investigated the role of a high Mg diet in two different mouse models of RA induced with the KRN serum, and collagen-induced arthritis. We also characterized the phenotypes of splenocytes, gene expression, and an extensive intestinal microbiome analyses including fecal material transplantation (FMT). …

Assessing The Contributions Of Modifiable Risk Factors To Serious Falls And Fragility Fractures Among Older Persons Living With Hiv, Julie A Womack, Terrence E Murphy, Linda Leo-Summers, Jonathan Bates, Samah Jarad, Thomas M Gill, Evelyn Hsieh, Maria C Rodriguez-Barradas, Phyllis C Tien, Michael T Yin, Cynthia A Brandt, Amy C Justice

Faculty, Staff and Students Publications

BACKGROUND: Although 50 years represents middle age among uninfected individuals, studies have shown that persons living with HIV (PWH) begin to demonstrate elevated risk for serious falls and fragility fractures in the sixth decade; the proportions of these outcomes attributable to modifiable factors are unknown.

METHODS: We analyzed 21,041 older PWH on antiretroviral therapy (ART) from the Veterans Aging Cohort Study from 01/01/2010 through 09/30/2015. Serious falls were identified by Ecodes and a machine-learning algorithm applied to radiology reports. Fragility fractures (hip, vertebral, and upper arm) were identified using ICD9 codes. Predictors for both models included a serious fall within …

Gpr43 Stimulation On Tcrαβ+ Intraepithelial Colonic Lymphocytes Inhibits The Recruitment Of Encephalitogenic T-Cells Into The Central Nervous System And Attenuates The Development Of Autoimmunity, Carolina Prado, Alexandra Espinoza, J Eduardo Martínez-Hernández, Joseph Petrosino, Erick Riquelme, Alberto J M Martin, Rodrigo Pacheco

Faculty, Staff and Students Publications

INTRODUCTION: Gut microbiota plays a critical role in the regulation of immune homeostasis. Accordingly, several autoimmune disorders have been associated with dysbiosis in the gut microbiota. Notably, the dysbiosis associated with central nervous system (CNS) autoimmunity involves a substantial reduction of bacteria belonging to Clostridia clusters IV and XIVa, which constitute major producers of short-chain fatty acids (SCFAs). Here we addressed the role of the surface receptor-mediated effects of SCFAs on mucosal T-cells in the development of CNS autoimmunity.

METHODS: To induce CNS autoimmunity, we used the mouse model of experimental autoimmune encephalomyelitis (EAE) induced by immunization with the myelin …

Functional Impact Of Ethyl-Β-D-Glucuronide On Mycobacterium Tuberculosis Stimulated Lung Macrophages, Charles Inaku

Biotechnology Theses

Chronic alcohol abuse has been shown to alter immune defense mechanisms in humans and mice which makes the host susceptible to infections, including Mycobacterium tuberculosis (Mtb) infection. However, limited information is available on the mechanisms involved in alcohol-mediated host immune system dysfunction.

In this study, we determined the effects of ethyl-β-d-glucuronide (EtG), an alcohol-derived metabolite, on immune response of mice lung macrophages. We measured cytokine and chemokine production by gamma-irradiated mtb (γ-mtb) stimulated mice lung macrophages in the presence or absence of EtG. We also determined the effect of EtG on the metabolic state of γ-mtb stimulated mice lung macrophages. …

Smarcb1 Regulates The Hypoxic Stress Response In Sickle Cell Trait, Melinda Soeung, Luigi Perelli, Ziheng Chen, Eleonora Dondossola, I-Lin Ho, Federica Carbone, Li Zhang, Hania Khan, Courtney N Le, Cihui Zhu, Michael D Peoples, Ningping Feng, Shan Jiang, Niki Millward Zacharias, Rosalba Minelli, Daniel D Shapiro, Angela K Deem, Sisi Gao, Emily H Cheng, Donatella Lucchetti, Cheryl L Walker, Alessandro Carugo, Virginia Giuliani, Timothy P Heffernan, Andrea Viale, Nizar M Tannir, Giulio F Draetta, Pavlos Msaouel, Giannicola Genovese

Faculty, Staff and Student Publications

Renal medullary carcinoma (RMC) is an aggressive kidney cancer that almost exclusively develops in individuals with sickle cell trait (SCT) and is always characterized by loss of the tumor suppressor SMARCB1. Because renal ischemia induced by red blood cell sickling exacerbates chronic renal medullary hypoxia in vivo, we investigated whether the loss of SMARCB1 confers a survival advantage under the setting of SCT. Hypoxic stress, which naturally occurs within the renal medulla, is elevated under the setting of SCT. Our findings showed that hypoxia-induced SMARCB1 degradation protected renal cells from hypoxic stress. SMARCB1 wild-type renal tumors exhibited lower levels …

Influenza C And D Viruses Demonstrated A Differential Respiratory Tissue Tropism In A Comparative Pathogenesis Study In Guinea Pigs, Chithra C. Sreenivasan, Runxia Liu, Rongyuan Gao, Yicheng Guo, Ben M. Hause, Milton Thomas, Ahsan Naveed, Travis Clement, Dana Rausch, Jane Christopher-Hennings, Eric Nelson, Julian Druce, Miaoyun Zhao, Radhey S. Kaushik, Qingsheng Li, Zizhang Sheng, Dan Dan, Feng Li

Nebraska Center for Virology: Faculty Publications

Influenza C virus (ICV) is increasingly associated with community-acquired pneumonia (CAP) in children and its disease severity is worse than the influenza B virus, but similar to influenza A virus associated CAP. Despite the ubiquitous infection landscape of ICV in humans, little is known about its replication and pathobiology in animals. The goal of this study was to understand the replication kinetics, tissue tropism, and pathogenesis of human ICV (huICV) in comparison to the swine influenza D virus (swIDV) in guinea pigs. Intranasal inoculation of both viruses did not cause clinical signs, however, the infected animals shed virus in nasal …

Evaluation Of 89zr-Labeled Anti-Pd-L1 Monoclonal Antibodies Using Dfo And Novel Hopo Analogues As Chelating Agents For Immuno-Pet, Bhasker Radaram, Sarah E Glazer, Ping Yang, Chia-Wei Li, Mien-Chie Hung, Seth T Gammon, Mian Alauddin, David Piwnica-Worms

Faculty, Staff and Student Publications

Programmed death ligand 1 (PD-L1) is a type 1 transmembrane immunosuppressive protein that is expressed on a wide range of cell types, including cancer cells. Anti-PD-L1 antibodies have revolutionized cancer therapy and have led to improved outcomes for subsets of cancer patients, including triple-negative breast cancer (TNBC) patients. As a result, PET imaging of PD-L1 protein expression in cancer patients has been explored for noninvasive detection of PD-L1 expressing tumors as well as monitoring response to anti-PD-L1 immune checkpoint therapy. Previous studies have indicated that the in vivo stability and in vivo target detection of antibody-based radio-conjugates can be dramatically …

Adenoviral-Vectored Epigraph Vaccine Elicits Robust, Durable, And Protective Immunity Against H3 Influenza A Virus In Swine, Erika M. Petro-Turnquist, Matthew J. Pekarek, Nicholas Jeanjaquet, Cedric Wooledge, David J. Steffen, Hiep Vu, Eric A. Weaver

Nebraska Center for Virology: Faculty Publications

Current methods of vaccination against swine Influenza A Virus (IAV-S) in pigs are infrequently updated, induce strain-specific responses, and have a limited duration of protection. Here, we characterize the onset and duration of adaptive immune responses after vaccination with an adenoviral-vectored Epigraph vaccine. In this longitudinal study we observed robust and durable antibody responses that remained above protective titers six months after vaccination. We further identified stable levels of antigen-specific T cell responses that remained detectable in the absence of antigen stimulation. Antibody isotyping revealed robust class switching from IgM to IgG induced by Epigraph vaccination, while the commercial comparator …

Development Of Combination Therapy Strategies To Treat Cancer Using Dihydroorotate Dehydrogenase Inhibitors, Nicholas Mullen

Theses & Dissertations

Cancer cells require supraphysiologic levels of nucleotide triphosphates to fuel their malignant behaviors, including uncontrolled proliferation, immune evasion, metastasis, and therapy resistance. This requirement is met by hyperactive flux through the de novo pyrimidine and de novo purine pathways. Dihydroorotate dehydrogenase (DHODH) is an essential enzyme in the de novo pyrimidine pathway that can be targeted by FDA approved and experimental drug compounds. A robust body of preclinical evidence, encompassing hundreds of independent studies over several decades, demonstrates impressive activity of DHODH inhibitors in animal models of cancer. Paradoxically, however, all clinical trials to date have failed to demonstrate efficacy …

A Novel Neuroinvasive Infection Modality For Francisella Tularensis Elicits Neuroinflammation Resulting In Cellular Damage, Mireya Griselle Ramos-Muniz

Open Access Theses & Dissertations

Francisella tularensis (Ft.) is a gram-negative coccobacillus bacterium that causes the zoonotic disease tularemia in humans. Ft. causes the most severe, often fatal, form of the disease through inhalation. However, Ft. is most commonly transmitted through direct contact with infected animal carcasses such as rodents and rabbits, consumption of contaminated food or water, or through arthropod bites, particularly ticks. Due to its extremely low infectious dose, high mortality rate, and potential use as a biological warfare agent, Ft. is classified by the CDC as a "Tier 1 select agent". Ft. infection triggers an overactive inflammatory response, termed a "cytokine storm", …

Investigating Novel Chemotherapeutics Against The Parasite Toxoplasma Gondii, Braydon Dreher

Theses/Capstones/Creative Projects

Toxoplasma gondii, an intracellular protozoan, is a globally prevalent parasite due to the infectivity of T. gondii with nearly 2.5 billion people affected worldwide. Toxoplasma gondii can cause toxoplasmosis, which is a disease acquired through the consumption of undercooked meat or found in the feces of felines, and often leads to profound neuropathology and potentially death. Currently, acute toxoplasmosis is treated with pyrimethamine and sulfadiazine, which is a combination of an antiprotozoal and a sulfonamide. This combination of drugs directly targets the acute stage of infection but has failed to eliminate or impact the chronic carriage of bradyzoites while …

Lymphatic Dysfunction And Associated Systemic Inflammation In Lymphedema, Assessed By Nirf-Li Imaging And Plasma Cytokine/Chemokine Analysis, Anna Vang

Dissertations and Theses (Open Access)

Breast cancer-related lymphedema (BCRL) manifests as swelling of the upper extremities and trunk as a result of lymphatic fluid buildup due to radiation therapy (RT), surgical lymph node removal, or chemotherapy. As there is currently no cure, BCRL treatment aims to improve quality of life (QOL). First-line treatment involves specialized massage therapy and the use of compression garments. Second-line treatments include reparative lymphatic microsurgeries such as lymphovenous bypass (LVB) and/or vascularized lymph node transplant (VLNT). There is a need for better understanding of the etiology of BCRL and lymphatic microsurgery outcomes. Blood specimens and near-infrared fluorescent lymphatic imaging (NIRF- LI)data …

Targeting Pd-L2-Rgmb Overcomes Microbiome-Related Immunotherapy Resistance, Joon Seok Park, Francesca S Gazzaniga, Meng Wu, Amalia K Luthens, Jacob Gillis, Wen Zheng, Martin W Lafleur, Sarah B Johnson, Golnaz Morad, Elizabeth M Park, Yifan Zhou, Stephanie S Watowich, Jennifer A Wargo, Gordon J Freeman, Dennis L Kasper, Arlene H Sharpe

Faculty, Staff and Student Publications

The gut microbiota is a crucial regulator of anti-tumour immunity during immune checkpoint inhibitor therapy. Several bacteria that promote an anti-tumour response to immune checkpoint inhibitors have been identified in mice1-6. Moreover, transplantation of faecal specimens from responders can improve the efficacy of anti-PD-1 therapy in patients with melanoma7,8. However, the increased efficacy from faecal transplants is variable and how gut bacteria promote anti-tumour immunity remains unclear. Here we show that the gut microbiome downregulates PD-L2 expression and its binding partner repulsive guidance molecule b (RGMb) to promote anti-tumour immunity and identify bacterial species that mediate this effect. PD-L1 and …

A Review Of Staphylococcus Aureus Pathogenesis, Global Impact, And The Rise Of Antibiotic-Resistant Clones, Anders Kleinbeck

Honors Scholar Theses

Staphylococcus aureus is a pathogen of grave concern to global public health. The pathogen has shown an unrivaled propensity to obtain resistance to nearly every antibiotic drug approved and prescribed for its treatment. This review will provide an overview of the history and evolution of S. aureus, including an analysis of its transition from the nosocomial setting to the community and the factors contributing to the species’ innate pathogenicity. This paper will also discuss the molecular mechanisms by which resistance to a wide range of popular antibiotic substances was obtained and will provide insight into the evolutionary patterns exhibited by …

Clinical Course Of A Patient With Agammaglobulinemia Caused By Slc39a7 Defect, Thao Le, Emily Farrow, Alvin Singh, Isabelle Thiffault, Nikita Raje

Posters

Case Report: A 10-year-old unimmunized boy initially presented to the hospital at 18-months of age with pneumonia and failure to thrive. He had multiple infections including Escherichia coli urosepsis, viral croup, chronic otitis media with bilateral ruptured tympanic membranes, and bacterial pneumonia. On physical examination, he was ill appearing and had diffuse crackles. His laboratory work-up showed leukocytosis, normocytic anemia, undetectable immunoglobulin (Ig) G, A, and E, low IgM (28 mg/dL), absent B cell with normal T cell (7800 mm3) and NK cell (527 mm3) counts, and low zinc level (63 mcg/dL). Genetic testing was negative for Bruton tyrosine kinase …

Irreversible Electroporation Potentiates Beta Glucan Induced Trained Innate Immunity: A Novel Combination Treatment For Pancreatic Adenocarcinoma., Matthew Woeste

Electronic Theses and Dissertations

Pancreatic cancer (PC) is a challenging diagnosis yet to benefit from advances in immune oncologic treatments. Irreversible electroporation, a non-thermal method of tumor ablation, is used in treatment of select patients with locally advanced unresectable PC and has potentiated the effect of certain immunotherapies. Yeast-derived particulate β-glucan induces trained innate immunity and successfully reduces murine PC tumor burden. This study tests the hypothesis that IRE may augment β-glucan-induced trained immunity in the treatment of PC. β-Glucan-trained pancreatic myeloid cells were evaluated ex vivo for trained responses and anti-tumor function after exposure to ablated and un-ablated tumor conditioned media. β-Glucan and …

Uncovering Novel Mechanism Of Immune Modulation Of Invariant Natural Killer T Cells By Liposomal Α-Galactosylceramide, Alexandra S. Flegle

Dissertations and Theses (Open Access)

Invariant Natural Killer T cells (iNK-T cells) are a powerful regulatory immune cell that can recruit both innate and adaptive immune cells. Unlike conventional T cells (CD4⁺ and CD8α⁺), they recognize glycolipid antigens via the MHC-class-I like molecule, CD1d. A synthetically derived glycolipid from the marine sponge, Agelas mauritianus, alpha-Galactosylceramide (α-GalCer) potently activates iNK-T cells. Within a few hours after activation, iNK-T cells produce high quantities of T_H1 and T_H2 type cytokines, thus shape subsequent adaptive immunity towards inflammation (T_H1) or immune-suppression (T_H2). Structural modification of α-GalCer’s phytosphingosine …

Bladder Mucosal Cystitis Cystica Lesions Are Tertiary Lymphoid Tissues That Correlate With Recurrent Urinary Tract Infection Frequency In Postmenopausal Women, Marianne M Ligon, Brooke Liang, Stacy M Lenger, Priyanka Parameswaran, Siobhan Sutcliffe, Jerry L Lowder, Indira U Mysorekar

Faculty, Staff and Students Publications

PURPOSE: We identify correlates and clinical outcomes of cystitis cystica, a poorly understood chronic inflammatory bladder change, in women with recurrent urinary tract infections.

MATERIALS AND METHODS: A retrospective, observational cohort of women with recurrent urinary tract infections who underwent cystoscopy (n=138) from 2015 to 2018 were identified using electronic medical records. Cystitis cystica status was abstracted from cystoscopy reports and correlations were identified by logistic regression. Urinary tract infection-free survival time associated with cystitis cystica was evaluated by Cox proportional hazards regression. Exact logistic regression was used to identify factors associated with changes to cystitis cystica lesions on repeat …

Comparison Of Maturation Stages Of Natural Killer Cell Differentiation Culture From Cultured And Freshly Isolated Umbilical Cord Blood Hematopoietic Stem Cells, Samuel Febrian Wijaya, Retno Lestari, Inna Rahmawati, Imelda Rosalyn Sianipar, Robby Nuraditya, Iqbal Fasha, Gita Pratama, Radiana Dhewayani Antarianto

Makara Journal of Health Research

Background: Natural killer (NK) cells originate from the differentiation of hematopoietic stem cells (HSCs) in the common lymphoid progenitor pathway, and HSCs can be obtained from umbilical cord blood (UCB). Comparative studies of NK cell differentiation between cultured and freshly isolated HSCs are important in the development of NK cell therapy for cancer. This study aimed to compare the maturation stages of NK cell differentiation between cultured and newly isolated HSC samples using interleukin-2 in the absence of feeder cells.

Methods: Differentiation cultures were divided into two groups according to HSC source. Giemsa staining and flow cytometry were …

Ido1 And Inflammatory Neovascularization: Bringing New Blood To Tumor-Promoting Inflammation, Alexander J. Muller, Arpita Mondal, Souvik Dey, George C Prendergast

Kimmel Cancer Center Faculty Papers

In parallel with the genetic and epigenetic changes that accumulate in tumor cells, chronic tumor-promoting inflammation establishes a local microenvironment that fosters the development of malignancy. While knowledge of the specific factors that distinguish tumor-promoting from non-tumor-promoting inflammation remains inchoate, nevertheless, as highlighted in this series on the 'Hallmarks of Cancer', it is clear that tumor-promoting inflammation is essential to neoplasia and metastatic progression making identification of specific factors critical. Studies of immunometabolism and inflamometabolism have revealed a role for the tryptophan catabolizing enzyme IDO1 as a core element in tumor-promoting inflammation. At one level, IDO1 expression promotes immune tolerance …