+publisher:"Cornell University" +contributor:("August, Avery")

Cornell University

1. Solouki, Sabrina. T CELL RECEPTOR SIGNAL STRENGTH AND ANTIGEN AFFINITY DIFFERENTIALLY REGULATE CD8+ MEMORY T CELL DEVELOPMENT.

Degree: PhD, Biomedical and Biological Sciences, 2020, Cornell University

URL: http://hdl.handle.net/1813/70427

► CD8+ T cells play a critical role in adaptive immunity by maintaining the ability to differentiate into CD8+ memory T cells, which provide the basis… (more)

▼ CD8+ T cells play a critical role in adaptive immunity by maintaining the ability to differentiate into CD8+ memory T cells, which provide the basis of protective immunity. During an intracellular infection, CD8+ T cells pass through several characteristic phases before becoming mature memory cells. Initial antigen stimulation causes naïve CD8+ T cells to clonally expand and differentiate into short-lived effector cells (SLECs). Subsequently, SLECs undergo a contraction phase, whereby the majority of surviving cells are known as memory precursor effector cells (MPECs); 5-10% of the MPECs survive the initial contraction phase from SLECs to further develop into CD8+ memory T cells. In my dissertation, we show that two distinct parameters: T cell Receptor (TcR) signal strength (regulated by the tyrosine kinase Itk) and antigen affinity, play important but separate roles in modulating the development of memory CD8+ T cells. We found that reducing both TcR signal strength and antigen affinity for the TcR leads to enhanced and accelerated development of CD8+ memory T cells. Additionally, TcR signal strength is able to regulate CD8+ T cell effector cytokine production independent of TcR antigen affinity. Analysis of RNA-sequencing data reveals that genes for inflammatory cytokines/cytokine receptors are significantly altered upon changes in antigen affinity and TcR signal strength. Furthermore, our findings show that the inflammatory milieu is critical in regulating this TcR signal strength mediated increase in memory development as both CpG treatment or co-transfer of WT and Itk-/- T cells eliminates the observed increase in memory cell formation. These findings suggest that TcR signal strength and antigen affinity independently contribute to CD8+ memory T cell development, which is modulated by inflammation, and suggest that manipulating TcR signal strength, along with antigen affinity, may be used to tune the development of CD8+ memory T cells during vaccine development. Advisors/Committee Members: August, Avery (chair), Rudd, Brian (committee member), Grimson, Andrew (committee member).

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APA (6^th Edition):

Solouki, S. (2020). T CELL RECEPTOR SIGNAL STRENGTH AND ANTIGEN AFFINITY DIFFERENTIALLY REGULATE CD8+ MEMORY T CELL DEVELOPMENT. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/70427

Chicago Manual of Style (16^th Edition):

Solouki, Sabrina. “T CELL RECEPTOR SIGNAL STRENGTH AND ANTIGEN AFFINITY DIFFERENTIALLY REGULATE CD8+ MEMORY T CELL DEVELOPMENT.” 2020. Doctoral Dissertation, Cornell University. Accessed February 28, 2021. http://hdl.handle.net/1813/70427.

MLA Handbook (7^th Edition):

Solouki, Sabrina. “T CELL RECEPTOR SIGNAL STRENGTH AND ANTIGEN AFFINITY DIFFERENTIALLY REGULATE CD8+ MEMORY T CELL DEVELOPMENT.” 2020. Web. 28 Feb 2021.

Vancouver:

Solouki S. T CELL RECEPTOR SIGNAL STRENGTH AND ANTIGEN AFFINITY DIFFERENTIALLY REGULATE CD8+ MEMORY T CELL DEVELOPMENT. [Internet] [Doctoral dissertation]. Cornell University; 2020. [cited 2021 Feb 28]. Available from: http://hdl.handle.net/1813/70427.

Council of Science Editors:

Solouki S. T CELL RECEPTOR SIGNAL STRENGTH AND ANTIGEN AFFINITY DIFFERENTIALLY REGULATE CD8+ MEMORY T CELL DEVELOPMENT. [Doctoral Dissertation]. Cornell University; 2020. Available from: http://hdl.handle.net/1813/70427

Cornell University

2. Mahamed, Deeqa. The 5'-Ectoenzyme Cd73 Promotes Toxoplasma Gondii Persistence In The Cns While Limiting Systemic Immunopathology.

Degree: PhD, Immunology, 2013, Cornell University

URL: http://hdl.handle.net/1813/33839

► The protozoan pathogen Toxoplasma gondii is a highly successful parasite that infects up to a third of the world's population, causing morbidity and mortality in… (more)

▼ The protozoan pathogen Toxoplasma gondii is a highly successful parasite that infects up to a third of the world's population, causing morbidity and mortality in the immunocompromised and when acquired congenitally. As an obligate intracellular pathogen, T. gondii has adapted to acquiring key nutrients from its host. Unlike vertebrate cells which are capable of de novo adenosine synthesis, T. gondii must rely solely on the purine salvage pathway, necessitating the presence of host-generated adenosine. CD73, present on vertebrate host cells but not T. gondii parasites, is a surface-anchored glycoprotein that catalyzes the conversion of AMP to adenosine, which is then sensed by the cell through transmembrane adenosine receptors. The enzyme is highly expressed in various tissues, including the brain, lymphoid organs, and in many immune cell subsets. To determine the role of CD73-generated adenosine in T. gondii infection, I infected wildtype and CD73-knockout mice with the Toxoplasma gondii ME49 strain via the oral route. CD73-/- mice did not succumb to reactivation of infection, and had fewer brain cysts developing in the CD73-/- mice. The reduced cyst burden was due to a defect in T. gondii differentiation to cyst-forming bradyzoites in the brain in the absence of CD73, and was independent of adenosine receptor signaling. In vitro differentiation in primary murine astrocytes and human fibroblasts was also CD73-dependent, and could be rescued by exogenous supplementation with adenosine or blocked with pharmacological inhibition of CD73, while treatment with an adenosine receptor agonist had no effect. Thus CD73- generated adenosine directly promoted T. gondii persistence and differentiation to long-lived tissue cysts. To further investigate the reason for the reduced parasite burden in the CNS, I inoculated WT and CD73-/- mice with T. gondii via peritoneal inoculation. Unexpectedly, CD73-/- mice were markedly susceptible to T. gondii intraperitoneal infection. Susceptibility was associated with elevated IL1[beta], TNF[alpha], IFN[gamma] and nitric oxide production, and increased infiltration of neutrophils and T cells into the peritoneal cavity. CD73 expression on both hematopoietic and nonhematopoietic cells was required to prevent immunopathology, and the absence of CD73 promoted local dissemination of the parasite. Thus, CD73 plays opposite functions in acute and chronic infections with a protozoan pathogen. Advisors/Committee Members: Bynoe, Margaret S. (chair), August, Avery (committee member), Denkers, Eric Young (committee member).

Subjects/Keywords: Toxoplasma gondii; Extracellular Adenosine; CD73

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APA (6^th Edition):

Mahamed, D. (2013). The 5'-Ectoenzyme Cd73 Promotes Toxoplasma Gondii Persistence In The Cns While Limiting Systemic Immunopathology. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/33839

Chicago Manual of Style (16^th Edition):

Mahamed, Deeqa. “The 5'-Ectoenzyme Cd73 Promotes Toxoplasma Gondii Persistence In The Cns While Limiting Systemic Immunopathology.” 2013. Doctoral Dissertation, Cornell University. Accessed February 28, 2021. http://hdl.handle.net/1813/33839.

MLA Handbook (7^th Edition):

Mahamed, Deeqa. “The 5'-Ectoenzyme Cd73 Promotes Toxoplasma Gondii Persistence In The Cns While Limiting Systemic Immunopathology.” 2013. Web. 28 Feb 2021.

Vancouver:

Mahamed D. The 5'-Ectoenzyme Cd73 Promotes Toxoplasma Gondii Persistence In The Cns While Limiting Systemic Immunopathology. [Internet] [Doctoral dissertation]. Cornell University; 2013. [cited 2021 Feb 28]. Available from: http://hdl.handle.net/1813/33839.

Council of Science Editors:

Mahamed D. The 5'-Ectoenzyme Cd73 Promotes Toxoplasma Gondii Persistence In The Cns While Limiting Systemic Immunopathology. [Doctoral Dissertation]. Cornell University; 2013. Available from: http://hdl.handle.net/1813/33839

Cornell University

3. Mohinta, Sonia. Role Of Aryl Hydrocarbon Receptor (Ahr) And The Effect Of Selective Ahr Modulators (Sahrms) On T Cell Differentiation And Effector Function.

Degree: PhD, Immunology, 2014, Cornell University

URL: http://hdl.handle.net/1813/36177

► A number of autoimmune and chronic inflammatory diseases are related to environmental stress. Aryl hydrocarbon receptor (AHR) is regarded as an environmental sensor integrating immune… (more)

▼ A number of autoimmune and chronic inflammatory diseases are related to environmental stress. Aryl hydrocarbon receptor (AHR) is regarded as an environmental sensor integrating immune responses with environmental stress and thereby influencing the extent of host immune response. The physiological role of AHR, particularly, in the immune response remains a key question after the discovery that AHR can modulate Th17/Treg axis in a ligand specific manner. However, discovery of a non-DRE mediated AHR activation in addition to its canonical DRE-mediated pathway further adds to this complexity thereby necessitating a more critical approach in delineating the role of AHR in the context of Th17/Treg balance. Selective AHR modulators (SAHRMs) are a recently identified class of compounds that are capable of binding to AHR and repress cytokine- driven gene expression without activating DRE-driven responses We have used three classes of AHR ligands namely agonist, antagonist and partial antagonist (SAHRM) to delineate the role of AHR in the context of Th17/Treg regulation both in vitro and in vivo. Here, we show that inhibition of the DRE-driven response is sufficient to suppress the Th17 differentiation. Also, we show that the suppression of Treg differentiation is dependent on the inhibition of the non-DRE mediated pathway. We have also delineated the role of DRE vs non-DRE driven responses of Th17 regulation in both an acute vs a chronic Th17 mediated diseases. In an acute inflammation using C. rodentium model of IBD (Inflammatory Bowel Disease) AHR agonist enhanced Th17 production and thereby promoted resolution of infection. On the other hand, using S. rectivirgula in a chronic mouse model of Hypersensitivity Pneumonitis we show that inhibition of DRE and /or non-DRE mediated response had minimal effect on IL-17A production but precludes Th17 plasticity by enabling secretion of alternate lineage antiinflammatory cytokines. This work has profound implication in pharmacological intervention in autoimmune and chronic inflammatory diseases by developing AHR compounds which can modulate DRE and non-DRE driven responses. Advisors/Committee Members: August, Avery (chair), Denkers, Eric Young (committee member), Bynoe, Margaret S. (committee member).

Subjects/Keywords: Aryl Hydrocarbon Receptor; Th17; Tcell differentiation

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APA (6^th Edition):

Mohinta, S. (2014). Role Of Aryl Hydrocarbon Receptor (Ahr) And The Effect Of Selective Ahr Modulators (Sahrms) On T Cell Differentiation And Effector Function. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/36177

Chicago Manual of Style (16^th Edition):

Mohinta, Sonia. “Role Of Aryl Hydrocarbon Receptor (Ahr) And The Effect Of Selective Ahr Modulators (Sahrms) On T Cell Differentiation And Effector Function.” 2014. Doctoral Dissertation, Cornell University. Accessed February 28, 2021. http://hdl.handle.net/1813/36177.

MLA Handbook (7^th Edition):

Mohinta, Sonia. “Role Of Aryl Hydrocarbon Receptor (Ahr) And The Effect Of Selective Ahr Modulators (Sahrms) On T Cell Differentiation And Effector Function.” 2014. Web. 28 Feb 2021.

Vancouver:

Mohinta S. Role Of Aryl Hydrocarbon Receptor (Ahr) And The Effect Of Selective Ahr Modulators (Sahrms) On T Cell Differentiation And Effector Function. [Internet] [Doctoral dissertation]. Cornell University; 2014. [cited 2021 Feb 28]. Available from: http://hdl.handle.net/1813/36177.

Council of Science Editors:

Mohinta S. Role Of Aryl Hydrocarbon Receptor (Ahr) And The Effect Of Selective Ahr Modulators (Sahrms) On T Cell Differentiation And Effector Function. [Doctoral Dissertation]. Cornell University; 2014. Available from: http://hdl.handle.net/1813/36177

Cornell University

4. Elmore, Sara. Immunity And Cell Signaling In The Host Response To Toxoplasma Gondii Infection.

Degree: PhD, Immunology, 2014, Cornell University

URL: http://hdl.handle.net/1813/38921

► The immune response to an invading pathogen must be tightly regulated so as to combat the infection while avoiding immune-mediated pathologies. This requires the coordinated… (more)

▼ The immune response to an invading pathogen must be tightly regulated so as to combat the infection while avoiding immune-mediated pathologies. This requires the coordinated response of both innate and adaptive immunity, involving an array of cell types, including T cells, macrophages, and dendritic cells. While many studies have examined the general host immune response to infection, this thesis aimed to more clearly dissect the roles of the chemokine receptor CXCR3 and [beta]-catenin in the coordination of this complex response by T cells and dendritic cells, respectively. I show that CXCR3 expression is required on CD4+ T cells for efficient clearance of the protozoan parasite Toxoplasma gondii during the intestinal response to infection. In the absence of this receptor, impaired CD4+ T cell-dependent IFN-[gamma] renders intestinal inflammatory monocytes inactive, and mice succumb to intestine-restricted overgrowth of parasite. Tissue resident dendritic cells are the first immune cells to recognize foreign antigen and are crucial to the initiation of adaptive immunity. I show that differentiation of CD8[alpha]+ and related CD103+ tissue resident DC subsets is positively regulated by [beta]catenin signaling, a pathway normally associated with tumorigenesis. Constitutive [beta]catenin signaling in DC thus leads to susceptibility of mice to Toxoplasma gondii infection by excessively promoting proinflammatory DC subsets in dependence on interferon regulatory factor (IRF) 8 expression, resulting in hyperactivation of CD4+ T cells. Interestingly, I show that [beta]-catenin signaling in bone marrow-derived DC (BMDC) displays the reverse phenotype, whereby antigen-specific T cell activation and cytokine production are impaired by these DC. This finding underscores the phenotypic and genetic variation among different DC subsets and that [beta]-catenin has the capacity to promote both inflammatory and tolerant DC subsets depending on context. The data in this thesis provide novel insight into the mechanisms of immune cell trafficking, signaling, and differentiation, which ultimately lead to host protection against microbial insult. Advisors/Committee Members: Denkers, Eric Young (chair), Wagner, Bettina (committee member), August, Avery (committee member).

Subjects/Keywords: Toxoplasma gondii; Immunity; Infection

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APA (6^th Edition):

Elmore, S. (2014). Immunity And Cell Signaling In The Host Response To Toxoplasma Gondii Infection. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/38921

Chicago Manual of Style (16^th Edition):

Elmore, Sara. “Immunity And Cell Signaling In The Host Response To Toxoplasma Gondii Infection.” 2014. Doctoral Dissertation, Cornell University. Accessed February 28, 2021. http://hdl.handle.net/1813/38921.

MLA Handbook (7^th Edition):

Elmore, Sara. “Immunity And Cell Signaling In The Host Response To Toxoplasma Gondii Infection.” 2014. Web. 28 Feb 2021.

Vancouver:

Elmore S. Immunity And Cell Signaling In The Host Response To Toxoplasma Gondii Infection. [Internet] [Doctoral dissertation]. Cornell University; 2014. [cited 2021 Feb 28]. Available from: http://hdl.handle.net/1813/38921.

Council of Science Editors:

Elmore S. Immunity And Cell Signaling In The Host Response To Toxoplasma Gondii Infection. [Doctoral Dissertation]. Cornell University; 2014. Available from: http://hdl.handle.net/1813/38921

Cornell University

5. Gebreselassie, Nebiat. The Eosinophil Regulates Immunity To The Parasitic Nematode Trichinella Spiralis.

Degree: PhD, Immunology, 2012, Cornell University

URL: http://hdl.handle.net/1813/31113

► Parasitic diseases pose a significant burden on the health of millions of people. Chronic helminth infections are typified by enhanced Th2 responses. Understanding how Th2… (more)

▼ Parasitic diseases pose a significant burden on the health of millions of people. Chronic helminth infections are typified by enhanced Th2 responses. Understanding how Th2 immunity is regulated is important for developing effective treatments for parasitic diseases and other Th2 disorders. Infection of mice with Trichinella spiralis is an especially useful model system to study the development of Th2 immunity to a natural pathogen. Eosinophilia is a prominent feature of T. spiralis infection, and we have shown previously that in eosinophilablated, transgenic mice, T. spiralis larvae die in large numbers in the muscle. Death is promoted by inducible nitric oxide synthase (iNOS). Neutrophils and F4/80+ CD11b+ Ly6C+ macrophages produced iNOS. Compared to fully developed muscle larvae, growing larvae were more susceptible to NO mediated killing in vitro. Larval growth was impaired in eosinophil-ablated mice, potentially extending the period of susceptibility to NO mediated killing. These changes were associated with reduced numbers of Th2 cells in infected muscle. Reduction in Th2 cell number was not caused by poor recruitment, but rather by impaired Th2 cell production in draining lymph nodes. Adding back eosinophils into [DELTA]dblGATA recipients improved parasite growth and survival, as well as Th2 cell accumulation, supporting the role of the eosinophil in parasite retention and local immune regulation. i The influence of Th2 immunity on parasite growth was tested using mice deficient in STAT6 and IL-13. The results reveal that the IL-4/STAT6 axis is a key pathway that regulates parasite growth. Transcription of genes associated with nutrient deprivation was increased in muscles of infected eosinophil-deficient mice, but glycogen content of muscle larvae and muscle tissue was not altered by eosinophil deficiency. Taken together, the results show that eosinophils and STAT6 promote parasite establishment in the muscle by promoting larval growth while coincidentally inhibiting the Th1 immune response. ii Advisors/Committee Members: Appleton, Judith Ann (chair), Russell, David G (committee member), August, Avery (committee member).

Subjects/Keywords: Trichinella; Nematode; Th2 immune response; stat6; Eosinophils; Nitric oxide; Glucose homeostasis

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APA (6^th Edition):

Gebreselassie, N. (2012). The Eosinophil Regulates Immunity To The Parasitic Nematode Trichinella Spiralis. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/31113

Chicago Manual of Style (16^th Edition):

Gebreselassie, Nebiat. “The Eosinophil Regulates Immunity To The Parasitic Nematode Trichinella Spiralis.” 2012. Doctoral Dissertation, Cornell University. Accessed February 28, 2021. http://hdl.handle.net/1813/31113.

MLA Handbook (7^th Edition):

Gebreselassie, Nebiat. “The Eosinophil Regulates Immunity To The Parasitic Nematode Trichinella Spiralis.” 2012. Web. 28 Feb 2021.

Vancouver:

Gebreselassie N. The Eosinophil Regulates Immunity To The Parasitic Nematode Trichinella Spiralis. [Internet] [Doctoral dissertation]. Cornell University; 2012. [cited 2021 Feb 28]. Available from: http://hdl.handle.net/1813/31113.

Council of Science Editors:

Gebreselassie N. The Eosinophil Regulates Immunity To The Parasitic Nematode Trichinella Spiralis. [Doctoral Dissertation]. Cornell University; 2012. Available from: http://hdl.handle.net/1813/31113

Cornell University

6. Ahn, Sung Ji. NON-LINEAR OPTICAL METHODS TO UNDERSTAND PATHOPHYSIOLOGY OF SMALL BLEEDS.

Degree: PhD, Biomedical Engineering, 2017, Cornell University

URL: http://hdl.handle.net/1813/59064

► Cerebral microhemorrhages (CMBs) are small hemorrhagic strokes found in the brain, also known as silent stroke since they do not illicit noticeable symptoms. Recently, due… (more)

Subjects/Keywords: cerebral micro bleeds; microgila; third harmonic generation; Biomedical engineering; Blood Flow; Multiphoton microscopy

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APA (6^th Edition):

Ahn, S. J. (2017). NON-LINEAR OPTICAL METHODS TO UNDERSTAND PATHOPHYSIOLOGY OF SMALL BLEEDS. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/59064

Chicago Manual of Style (16^th Edition):

Ahn, Sung Ji. “NON-LINEAR OPTICAL METHODS TO UNDERSTAND PATHOPHYSIOLOGY OF SMALL BLEEDS.” 2017. Doctoral Dissertation, Cornell University. Accessed February 28, 2021. http://hdl.handle.net/1813/59064.

MLA Handbook (7^th Edition):

Ahn, Sung Ji. “NON-LINEAR OPTICAL METHODS TO UNDERSTAND PATHOPHYSIOLOGY OF SMALL BLEEDS.” 2017. Web. 28 Feb 2021.

Vancouver:

Ahn SJ. NON-LINEAR OPTICAL METHODS TO UNDERSTAND PATHOPHYSIOLOGY OF SMALL BLEEDS. [Internet] [Doctoral dissertation]. Cornell University; 2017. [cited 2021 Feb 28]. Available from: http://hdl.handle.net/1813/59064.

Council of Science Editors:

Ahn SJ. NON-LINEAR OPTICAL METHODS TO UNDERSTAND PATHOPHYSIOLOGY OF SMALL BLEEDS. [Doctoral Dissertation]. Cornell University; 2017. Available from: http://hdl.handle.net/1813/59064

Cornell University

7. Kim, Do-Geun. The Role Of Extracellular Adenosine In Regulation Of Paracellular And Transcellular Permeability Of Blood Brain Barrier.

Degree: PhD, Veterinary Medicine, 2015, Cornell University

URL: http://hdl.handle.net/1813/40912

► The brain is the center of cognitive function and also regulates the physiology of the body. Due to its importance, it requires special vascular structure… (more)

▼ The brain is the center of cognitive function and also regulates the physiology of the body. Due to its importance, it requires special vascular structure which separates itself from the peripheral circulation to maintain its electrical physiology and protect from insult from circulation. The vasculature of the brain is lined with a single layer of endothelial cells which is sealed with adherent and tight junction molecules. The endothelial cell lining is further insulated with pericytes and astrocytic endfeet. Also endothelial cells express varieties of transporters which selectively allow the entrance of molecules into the brain. This physicochemical vascular entity is called the blood brain barrier. This structural barrier is, however, detrimental in the delivery of molecules to the brain. Many of drugs are dropped out from the pipelines because they cannot show the expected effect in the brain. To overcome this, many approaches were devised to increase the drug delivery to the brain, they were either invasive or ineffective. In previous study, we have shown that adenosine receptor signaling can increase the permeability of large molecules to the brain. Adenosine receptor is the G-protein coupled receptor which is involved in numerous physiological reactions. Activation of adenosine receptor showed potent and reversible increased permeability to the large molecules. In this dissertation, we aimed to reveal if activation of adenosine receptor signaling can increase the permeability in the human primary brain endothelial cell monolayer. Indeed we observed robust and reversible permeability increase in human brain endothelial cells. This was mediated by increased Rho-GTPase activity and following stress fiber formation which subsequently disrupted the tight and adherens junctional molecules. Activation of AR also increased the permeability to chemotherapeutics Gemcitabine. Also, we studied if adenosine receptor signaling can increase transcellular pathway which is mainly mediated by transporters highly expressed on the brain endothelial cells, especially P-glycoprotein. Indeed we observed that AR activation can increase the accumulation of the P-glycoprotein substrate in human primary brain endothelial cells by down regulating the expression and function of P-glycoprotein. Also, we could observe that it down-regulates the P-glycoprotein and thereby increase the accumulation of epirubicin, a P-glycoprotein substrate, in the brain of the mouse. Collectively, we showed that AR activation can increase the permeability paracellular permeability of the human primary brain endothelial cells and also down regulate the P-glycoprotein function and enhance the transcellular permeability. These dual mechanism of regulating the permeability of the blood brain barrier might be beneficial in drug delivery in the brain which will benefit millions of patients suffering from the neurodegenerative disease or brain cancers. Advisors/Committee Members: Bynoe,Margaret S. (chair), Clark,Theodore G. (committee member), August,Avery (committee member).

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APA (6^th Edition):

Kim, D. (2015). The Role Of Extracellular Adenosine In Regulation Of Paracellular And Transcellular Permeability Of Blood Brain Barrier. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/40912

Chicago Manual of Style (16^th Edition):

Kim, Do-Geun. “The Role Of Extracellular Adenosine In Regulation Of Paracellular And Transcellular Permeability Of Blood Brain Barrier.” 2015. Doctoral Dissertation, Cornell University. Accessed February 28, 2021. http://hdl.handle.net/1813/40912.

MLA Handbook (7^th Edition):

Kim, Do-Geun. “The Role Of Extracellular Adenosine In Regulation Of Paracellular And Transcellular Permeability Of Blood Brain Barrier.” 2015. Web. 28 Feb 2021.

Vancouver:

Kim D. The Role Of Extracellular Adenosine In Regulation Of Paracellular And Transcellular Permeability Of Blood Brain Barrier. [Internet] [Doctoral dissertation]. Cornell University; 2015. [cited 2021 Feb 28]. Available from: http://hdl.handle.net/1813/40912.

Council of Science Editors:

Kim D. The Role Of Extracellular Adenosine In Regulation Of Paracellular And Transcellular Permeability Of Blood Brain Barrier. [Doctoral Dissertation]. Cornell University; 2015. Available from: http://hdl.handle.net/1813/40912

Cornell University

8. Carter, Chavez. Role Of Itk In Th17 Mediated Inflammation Model Hypersensitivity Pneumonitis.

Degree: PhD, Immunology, 2015, Cornell University

URL: http://hdl.handle.net/1813/41075

► Hypersensitivity Pneumonitis (HP) is a lung disease caused by repeated inhalation of environmental antigens leading to inflammation, tissue scarring, and some loss of lung function.… (more)

▼ Hypersensitivity Pneumonitis (HP) is a lung disease caused by repeated inhalation of environmental antigens leading to inflammation, tissue scarring, and some loss of lung function. This pathology is believed to be due to the increased IL-17A, a cytokine secreted predominantly by a subset of T cells, Th17 cells, that induces recruitment of inflammatory cells such as neutrophils and leads to pathology in this disease. The thermophile Sacharopolyspora rectivigula (SR) causes HP in humans, and we have used a murine model of HP, exposure to SR, to study the molecular mechanism of disease development. Using novel IL-17A-GFP reporter mice, our preliminary data suggests that the high levels of IL-17A induced in response to SR are produced in part by CD4+ T cells and not by neutrophils. The Tec family tyrosine kinase Itk is a pharmaceutical target and regulates T cell activation and cytokine production, including Th2 cytokines and IL-17A in conventional Th17 cells. Mice lacking Itk are therefore resistant to developing Th2 cytokine driven allergic lung inflammation. However our experiments indicate that mice lacking Itk develop HP. Histology from these mice indicates an increase in inflammatory cells in lung airways as well as deterioration of lung tissue architecture. Mice lacking Itk also have significant levels of IL-17A mRNA expression in the lung, and an increase in the number of CD4+ IL-17A producing cells. Furthermore, the lack of Itk signaling led to the absence of IL-17A producing [gamma][delta] T cells in the early stage of HP, which recover over the later stage of disease. This phenomenon directly coincides with the emergence of IL-17A producing CD4+[gamma][delta] T cells in the lungs of Itk-/- mice exposed to SR. We conclude that Itk regulated signals are not critical for the production of IL-17A in response to SR, and Itk may therefore differentially regulate the production of IL-17A in different types of T cells. We also show that the inhibition of Itk kinase signaling can be inhibited by targeting allele sensitive Itkas. The block in kinase activity leads to decrease response of response in the BAL and lungs. We investigate the relationship between Th17 cell and T regulatory T cells in an IL-17A driven disease as it relates to Itk signaling. We find that Itk signaling is not altering the proportion or numbers of T regulatory cells. Additionally, we show that iNKT cells are a possible source of IL-17A and this primarily independent of Itk signal as well. Lastly, we investigate the role of IL4Ra signaling and indirectly innate memory phenotype (IMP) cells in HP. Our data shows IL-4 signaling as well as IMP cells play a protective role in the BAL during HP. Furthermore, IL-4Ra and IMP cells are partially responsible for the number of CD4+ T cells seen in HP, which is independent of Itk-/- mice ability to make IL-17A cytokine in SR induced HP. SR induced HP. ! Together, you data show Itk mediate differential immune responses in Advisors/Committee Members: August,Avery (chair), Bynoe,Margaret S. (committee member), Rudd,Brian D (committee member).

Subjects/Keywords: Itk; Hypersensitivity Pneumonitis; T cells

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APA (6^th Edition):

Carter, C. (2015). Role Of Itk In Th17 Mediated Inflammation Model Hypersensitivity Pneumonitis. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/41075

Chicago Manual of Style (16^th Edition):

Carter, Chavez. “Role Of Itk In Th17 Mediated Inflammation Model Hypersensitivity Pneumonitis.” 2015. Doctoral Dissertation, Cornell University. Accessed February 28, 2021. http://hdl.handle.net/1813/41075.

MLA Handbook (7^th Edition):

Carter, Chavez. “Role Of Itk In Th17 Mediated Inflammation Model Hypersensitivity Pneumonitis.” 2015. Web. 28 Feb 2021.

Vancouver:

Carter C. Role Of Itk In Th17 Mediated Inflammation Model Hypersensitivity Pneumonitis. [Internet] [Doctoral dissertation]. Cornell University; 2015. [cited 2021 Feb 28]. Available from: http://hdl.handle.net/1813/41075.

Council of Science Editors:

Carter C. Role Of Itk In Th17 Mediated Inflammation Model Hypersensitivity Pneumonitis. [Doctoral Dissertation]. Cornell University; 2015. Available from: http://hdl.handle.net/1813/41075

Cornell University

9. Mohanan Nair Padmini, Sunish. Role Of Peptidylarginine Deiminase 2 (Pad2) In Epithelial Carcinogenesis And Tumor-Associated Inflammation.

Degree: PhD, Veterinary Medicine, 2014, Cornell University

URL: http://hdl.handle.net/1813/36176

► Numerous recent studies have shown that epigenetic modifications play a significant role in cancer pathogenesis. The PADs are a family of epigenetic enzymes that catalyze… (more)

▼ Numerous recent studies have shown that epigenetic modifications play a significant role in cancer pathogenesis. The PADs are a family of epigenetic enzymes that catalyze citrullination, a reaction by which PADs convert peptidyl-arginine to neutral citrulline, leading to the disruption of protein-protein interactions. Our lab has found that PAD2 has a critical role in breast cancer progression. The goal of this thesis research was to further elucidate the role of PAD2 in epithelial carcinogenesis using PAD2 overexpression tumor cell lines and a MMTV-FLAG-hPAD2 transgenic mouse model. We also aimed to evaluate how PAD2 may play a direct role in regulating chronic inflammation via macrophage extracellular chromatin trap release ("ETosis"). Interestingly, we found that 40% of the MMTV-FLAG-hPAD2 overexpressing transgenic mice developed proliferative skin lesions after five months of age. The tumors expressed the transgenic form of FLAG-hPAD2 and showed increased expression for inflammatory cytokines such as IL6 and IL8. As the next step we conducted a two-stage chemical carcinogenesis study to further evaluate the predilection of MMTV-FLAG-hPAD2 mice to develop more invasive skin tumors and compare the histopathology of these tumors with the WT tumors. We found that a higher percentage of MMTV-FLAG-hPAD2 mice developed skin papillomas and the transgenic tumors were more invasive. Furthermore, hPAD2 expression levels were highly positively correlated with chemokine levels and negatively correlated with the cell adhesion markers suggesting the role of PAD2 in assisting epithelial-mesenchymal transition. We had previously shown that PAD4 isozyme in neutrophils is involved in chromatin decondensation and extracellular chromatin trap release. In this thesis research we provide evidence on how PAD2 is involved in macrophage extracellular trap (MET) release. Using in vitro macrophage culture models, we found that PAD2 is critical in functional MET release and that METs contain high levels of histone H4 citrulline 3 (H4Cit3) modification. Using human tongue SCC tissue, we show that CD68+ macrophage associated ETs exist in tumor tissue and are highly positive for citrullinated histones. Additionally, we show that PAD2-rich macrophages associated with chronic subclinical inflammation in adipose tissue also release METs suggesting the significant role of PAD2 in chronic inflammation via MET release. Collectively, these studies provide strong experimental evidence establishing PAD2 as a potential oncogene, a therapeutic target for immunomodulation and a regulator of obesity and tumor associated inflammation. Advisors/Committee Members: Coonrod, Scott A. (chair), August, Avery (committee member), Fischbach, Claudia (committee member), Weiss, Robert S. (committee member).

Subjects/Keywords: Peptidylarginine deiminase 2 (PAD2); Cancer progression; Extracellular chromatin traps (ETosis)

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APA (6^th Edition):

Mohanan Nair Padmini, S. (2014). Role Of Peptidylarginine Deiminase 2 (Pad2) In Epithelial Carcinogenesis And Tumor-Associated Inflammation. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/36176

Chicago Manual of Style (16^th Edition):

Mohanan Nair Padmini, Sunish. “Role Of Peptidylarginine Deiminase 2 (Pad2) In Epithelial Carcinogenesis And Tumor-Associated Inflammation.” 2014. Doctoral Dissertation, Cornell University. Accessed February 28, 2021. http://hdl.handle.net/1813/36176.

MLA Handbook (7^th Edition):

Mohanan Nair Padmini, Sunish. “Role Of Peptidylarginine Deiminase 2 (Pad2) In Epithelial Carcinogenesis And Tumor-Associated Inflammation.” 2014. Web. 28 Feb 2021.

Vancouver:

Mohanan Nair Padmini S. Role Of Peptidylarginine Deiminase 2 (Pad2) In Epithelial Carcinogenesis And Tumor-Associated Inflammation. [Internet] [Doctoral dissertation]. Cornell University; 2014. [cited 2021 Feb 28]. Available from: http://hdl.handle.net/1813/36176.

Council of Science Editors:

Mohanan Nair Padmini S. Role Of Peptidylarginine Deiminase 2 (Pad2) In Epithelial Carcinogenesis And Tumor-Associated Inflammation. [Doctoral Dissertation]. Cornell University; 2014. Available from: http://hdl.handle.net/1813/36176

Cornell University

10. Huang, Weishan. Function Of Il-2-Inducible T Cell Kinase (Itk) In Innate T Cells And Mast Cells.

Degree: PhD, Pharmacology, 2014, Cornell University

URL: http://hdl.handle.net/1813/36191

► IL-2-inducible T cell kinase (ITK) is expressed in T lymphocytes and mast cells (MC), and functions as a critical signaling mediator downstream of numerous cell… (more)

▼ IL-2-inducible T cell kinase (ITK) is expressed in T lymphocytes and mast cells (MC), and functions as a critical signaling mediator downstream of numerous cell surface receptors. ITK regulates both adaptive and innate immunity, via regulation of cell differentiation and activation. Lack of ITK results in spontaneous memory acquisition in [alpha][beta] T cells termed "innate memory phenotype (IMP) T cells". The development and function of IMP T cells, and the role of ITK in their development remains unknown. This dissertation describes an alternative bone marrow transplantation system, which generates murine models with predominant naïve or IMP T cells, allowing comparative investigation of the functions of these cells in vivo; and demonstrates that: 1) IMP T cell development requires hematopoietic expression of major histocompatibility complexes; 2) IMP CD8+ T cells are not the result of T cell homeostatic proliferation (HP), and they can rapidly and potently respond to primary antigenic stimulation; and 3) IMP CD4+ T cells can suppress autoimmune graft-versus-host disease. In addition, this dissertation also investigates the T cell-intrinsic role of ITK in the development of both IMP and HP CD8+ T cells: 1) ITK tunes IL-4/TcR signaling synergy to regulate IMP CD8+ T cell differentiation; and 2) ITK suppresses CD8+ T cell HP and anti-tumor immunity. Loss of ITK in mice also results in hyper-production of immunoglobulin E (IgE), through which MC regulate the development of allergy. Differential functions of ITK and the homologous Bruton's tyrosine kinase (BTK) in MC response to allergen/IgE-mediated stimulation have been illustrated. This dissertation further shows a redundant function for ITK/BTK in MC response to the bacterial endotoxin lipopolysaccharide (LPS), in that lack of ITK and BTK leads to hyper-production of MC-derived TNF-[alpha], which exacerbates LPS-induced septic hypothermia. This work provides insights into the function of ITK in innate T cells, and the value of targeting ITK to enhance antigen-specific primary response by IMP CD8+ T cells, regulatory function of IMP CD4+ T cells, and expansion of anti-tumor HP CD8+ T cells, for therapeutic purposes. However, the MC response to LPS also raises concern on the potential use of ITK/BTK cross-reactive kinase inhibitors. Advisors/Committee Members: August, Avery (chair), Collins, Ruth N. (committee member), Yen, Andrew (committee member), Leifer, Cynthia Anne (committee member), Linder, Maurine E. (committee member).

Subjects/Keywords: IL-2-inducible T cell kinase (ITK); Innate T cells; Mast cells

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APA (6^th Edition):

Huang, W. (2014). Function Of Il-2-Inducible T Cell Kinase (Itk) In Innate T Cells And Mast Cells. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/36191

Chicago Manual of Style (16^th Edition):

Huang, Weishan. “Function Of Il-2-Inducible T Cell Kinase (Itk) In Innate T Cells And Mast Cells.” 2014. Doctoral Dissertation, Cornell University. Accessed February 28, 2021. http://hdl.handle.net/1813/36191.

MLA Handbook (7^th Edition):

Huang, Weishan. “Function Of Il-2-Inducible T Cell Kinase (Itk) In Innate T Cells And Mast Cells.” 2014. Web. 28 Feb 2021.

Vancouver:

Huang W. Function Of Il-2-Inducible T Cell Kinase (Itk) In Innate T Cells And Mast Cells. [Internet] [Doctoral dissertation]. Cornell University; 2014. [cited 2021 Feb 28]. Available from: http://hdl.handle.net/1813/36191.

Council of Science Editors:

Huang W. Function Of Il-2-Inducible T Cell Kinase (Itk) In Innate T Cells And Mast Cells. [Doctoral Dissertation]. Cornell University; 2014. Available from: http://hdl.handle.net/1813/36191

Cornell University

11. Wang, Jie. MECHANISMS UNDERLYING NEONATAL CD8+ T CELL DEVELOPMENT AND RESPONSES.

Degree: PhD, Immunology and Infectious Disease, 2017, Cornell University

URL: http://hdl.handle.net/1813/59007

► Neonatal infection is a major cause of morbidity and mortality worldwide. While adults generate robust immunity to most intracellular pathogens, neonates have an impaired ability… (more)

▼ Neonatal infection is a major cause of morbidity and mortality worldwide. While adults generate robust immunity to most intracellular pathogens, neonates have an impaired ability to generate long-lasting immunity. As CD8+ T cells are essential for clearing intracellular pathogens, it is crucial to understand why these cells behave differently during infection in early life. We previously showed that neonatal CD8+ T cells rapidly become terminally differentiated and fail to form long-term memory following infection. However, the underlying basis for these age-related differences is unclear. In this thesis, experiments were designed to investigate how neonatal and adult CD8+ T cells behave differently and what underlying mechanisms contribute to these differences. We demonstrated that different aged CD8+ T cell progenitors have different gene expression profiles. Different aged progenitors also give rise to CD8+ T cells with distinct characteristics in the periphery when developed in the same thymic environment. Ectopic expression of the developmentally regulated protein Lin28b in adult CD8+ T cells granted them neonate-like traits. Our data indicate that different aged CD8+ T cells behave differently because they have different origins and Lin28b may regulate CD8+ T cell behaviors in early life. Neonatal CD8+ T cells also acquire a much more active metabolic profile compared to adult CD8+ T cells, which may contribute to their rapid contraction and poor memory formation following infection. Extrinsic differences between different aged animals were also studied by transferring adult CD8+ T cells into neonatal mice. Neonatal environment was able to modify adult CD8+ T cells to become phenotypically and functionally different. Neonatal-experienced adult CD8+ T cells proliferated more rapidly and formed insufficient memory. These findings suggest that in addition to cell-intrinsic factors, extrinsic factors may also contribute to age-related differences in CD8+ T cell behaviors. In summary, these findings advance our knowledge of neonatal CD8+ T cell responses and cast light on potential therapeutic targets early in life, such as Lin28b, mTOR and components of metabolic pathways. A more thorough understanding of neonatal immune responses is pivotal for combating diseases in neonates and improving their wellbeing. Advisors/Committee Members: Rudd, Brian D. (chair), Lee, Siu Sylvia (committee member), Flaminio, Maria Julia Bevilaqua Felippe (committee member), August, Avery (committee member).

Subjects/Keywords: Immunology

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Wang, J. (2017). MECHANISMS UNDERLYING NEONATAL CD8+ T CELL DEVELOPMENT AND RESPONSES. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/59007

Chicago Manual of Style (16^th Edition):

Wang, Jie. “MECHANISMS UNDERLYING NEONATAL CD8+ T CELL DEVELOPMENT AND RESPONSES.” 2017. Doctoral Dissertation, Cornell University. Accessed February 28, 2021. http://hdl.handle.net/1813/59007.

MLA Handbook (7^th Edition):

Wang, Jie. “MECHANISMS UNDERLYING NEONATAL CD8+ T CELL DEVELOPMENT AND RESPONSES.” 2017. Web. 28 Feb 2021.

Vancouver:

Wang J. MECHANISMS UNDERLYING NEONATAL CD8+ T CELL DEVELOPMENT AND RESPONSES. [Internet] [Doctoral dissertation]. Cornell University; 2017. [cited 2021 Feb 28]. Available from: http://hdl.handle.net/1813/59007.

Council of Science Editors:

Wang J. MECHANISMS UNDERLYING NEONATAL CD8+ T CELL DEVELOPMENT AND RESPONSES. [Doctoral Dissertation]. Cornell University; 2017. Available from: http://hdl.handle.net/1813/59007

12. Yan, Angela. THE ROLE OF CD73 IN GLIOBLASTOMA PATHOGENESIS AND ANTI-GLIOBLASTOMA IMMUNE RESPONSE.

Degree: PhD, Biomedical and Biological Sciences, 2019, Cornell University

URL: http://hdl.handle.net/1813/67210

► CD73 is a key enzyme in extracellular ATP metabolism; it converts AMP to extracellular adenosine. CD73 is involved in many cellular functions, including cell adhesion,… (more)

▼ CD73 is a key enzyme in extracellular ATP metabolism; it converts AMP to extracellular adenosine. CD73 is involved in many cellular functions, including cell adhesion, cell proliferation, tumor invasion, and angiogenesis. Because of its enzymatic activity, CD73 is also a key immune regulator. CD73-generated extracellular adenosine signals through the A2A adenosine receptor (AR) on leukocytes to attenuate inflammation and restore immune homeostasis. Because of these properties, CD73 is used by tumor cells to promote their pathogenesis and attenuate the host anti-tumor immune response. In this dissertation, we investigated the role of CD73 in glioblastoma (GB) pathogenesis and anti-GB immune response. We implanted mouse GB cells in wild type (WT) and CD73-/- mice. We found that GB-bearing CD73-/- mice had reduced tumor size and invasiveness and decreased tumor vessel density compared with GB-bearing WT mice. To investigate whether host CD73 promoted GB invasiveness, we generated the CD73-FLK mice from the CD73-/- mice by enforcing CD73 expression on endothelial cells. GB-bearing CD73-FLK mice had the most invasive tumors compared with GB-bearing WT and CD73-/- mice, suggesting that the limited host CD73 on endothelial cells increased GB invasiveness. We also found a 20-fold upregulation of the A2B AR in GB, which is rarely expressed in the central nervous system under physiological conditions and only upregulated during pathological conditions. Inhibition of A2B AR signaling decreased the permeability glycoprotein (P-gp) and the multidrug resistance-associated protein 1 (MRP1) expression on mouse GB cells and made GB cells more susceptible to temozolomide-induced cell death. Additionally, we found that GB-bearing CD73-/- mice mounted a stronger inflammatory response to GB than GB-bearing WT mice. Compared with GB-bearing WT mice, GB-bearing CD73-/- mice had increased anti-inflammatory cytokine IL-10 and reduced pro-inflammatory cytokines TNF-α and IL-1β. Further, GB-infiltrating regulatory T cells and M2 microglia/macrophages were reduced in GB-bearing CD73-/- mice, whereas GB-infiltrating CD8+ T cells were increased. Together, these findings suggest that CD73 is used by GB to promote its pathogenesis through increasing GB angiogenesis, invasion, and chemoresistance. Our data also suggest that GB evades the host immune response by using CD73 to attenuate inflammatory responses. Therefore, targeting the CD73-AR axis presents great potentials for future GB therapeutic interventions. Advisors/Committee Members: Bynoe, Margaret S. (chair), Clark, Theodore G. (committee member), August, Avery (committee member), Rudd, Brian D. (committee member).

Subjects/Keywords: Immunology; A2B adenosine receptor; cancer immunology; CD73; extracellular adenosine; glioblastoma; glioma chemoresistance; Oncology

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APA (6^th Edition):

Yan, A. (2019). THE ROLE OF CD73 IN GLIOBLASTOMA PATHOGENESIS AND ANTI-GLIOBLASTOMA IMMUNE RESPONSE. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/67210

Chicago Manual of Style (16^th Edition):

Yan, Angela. “THE ROLE OF CD73 IN GLIOBLASTOMA PATHOGENESIS AND ANTI-GLIOBLASTOMA IMMUNE RESPONSE.” 2019. Doctoral Dissertation, Cornell University. Accessed February 28, 2021. http://hdl.handle.net/1813/67210.

MLA Handbook (7^th Edition):

Yan, Angela. “THE ROLE OF CD73 IN GLIOBLASTOMA PATHOGENESIS AND ANTI-GLIOBLASTOMA IMMUNE RESPONSE.” 2019. Web. 28 Feb 2021.

Vancouver:

Yan A. THE ROLE OF CD73 IN GLIOBLASTOMA PATHOGENESIS AND ANTI-GLIOBLASTOMA IMMUNE RESPONSE. [Internet] [Doctoral dissertation]. Cornell University; 2019. [cited 2021 Feb 28]. Available from: http://hdl.handle.net/1813/67210.

Council of Science Editors:

Yan A. THE ROLE OF CD73 IN GLIOBLASTOMA PATHOGENESIS AND ANTI-GLIOBLASTOMA IMMUNE RESPONSE. [Doctoral Dissertation]. Cornell University; 2019. Available from: http://hdl.handle.net/1813/67210

13. Purwada, Alberto. Bioengineered Immune Organoids for Controlling B Cell Development.

Degree: PhD, Biomedical Engineering, 2017, Cornell University

URL: http://hdl.handle.net/1813/56816

► The humoral arm of the adaptive immune system works by producing antigen-specific antibody to clear pathogens from the extracellular spaces in the body. The humoral… (more)

▼ The humoral arm of the adaptive immune system works by producing antigen-specific antibody to clear pathogens from the extracellular spaces in the body. The humoral immunity requires the germinal center (GC) reaction to enable the formation of antibody-secreting cells and the production of antibodies that can bind the target antigen and trigger the appropriate immune responses. GC is a microanatomical structure in the B cell follicle that transiently arises from lymphocyte proliferation over the course of humoral immune response. While in vivo models have provided us with new insights regarding the GC reaction, there is a lack of ex vivo systems that can be utilized to model the GC process. Existing techniques do not fully recapitulate the lymphoid niche or require implantation into live animal models. It is thus challenging to assess the specific signals that control GC reaction, analyze the heterogeneous GC B cell population, and understand the decision-making process that determines GC B cell fate. In order to address these limitations, we have developed immune organoids to recapitulate key GC characteristics and control B cell activation in culture. We first analyzed the techniques that have been used to engineer B cell phenotype (Chapter 1). Inspired by the role of integrin in cell microenvironment, we utilized the gelatin matrix to enhance GC-like B cell expansion in culture (Chapter 2). We next showed that ex vivo GC-like B cells were comparable to in vivo GC B cells and could be used to study the GC cell cycle regulation (Chapter 3). We then used the modular immune organoid to assess the role of integrin ligand specificity in modulating GC-like B cell phenotype (Chapter 4). Finally, we demonstrated that B Cell Receptor (BCR) stimulation could induce ASC differentiation and facilitate the enrichment of antigen-specific GC-like B cells in the presence of a negative selection pressure (Chapter 5). Having described the works done to develop an improved B cell culture system, we concluded this dissertation with a reflection on the research journey and some suggestions regarding the next key steps to continue this project (Chapter 6). In the long term, we believe that the immune organoid platform could be used to obtain mechanistic insights about the adaptive immune system generation, understand the decision-making process in GC reaction, model lymphoid transformations that trigger certain diseases, and identify therapeutic agents that can interact with the immune system. Advisors/Committee Members: Singh, Ankur (chair), August, Avery (committee member), Weiss, Robert S. (committee member), Putnam, David A. (committee member).

Subjects/Keywords: Biomedical engineering; 3D Cell Culture; B Cells; Germinal Center; Lymphoid Tissues; Tissue Engineering

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APA (6^th Edition):

Purwada, A. (2017). Bioengineered Immune Organoids for Controlling B Cell Development. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/56816

Chicago Manual of Style (16^th Edition):

Purwada, Alberto. “Bioengineered Immune Organoids for Controlling B Cell Development.” 2017. Doctoral Dissertation, Cornell University. Accessed February 28, 2021. http://hdl.handle.net/1813/56816.

MLA Handbook (7^th Edition):

Purwada, Alberto. “Bioengineered Immune Organoids for Controlling B Cell Development.” 2017. Web. 28 Feb 2021.

Vancouver:

Purwada A. Bioengineered Immune Organoids for Controlling B Cell Development. [Internet] [Doctoral dissertation]. Cornell University; 2017. [cited 2021 Feb 28]. Available from: http://hdl.handle.net/1813/56816.

Council of Science Editors:

Purwada A. Bioengineered Immune Organoids for Controlling B Cell Development. [Doctoral Dissertation]. Cornell University; 2017. Available from: http://hdl.handle.net/1813/56816

14. Pomeroy, Brianna Joy. LATE GESTATION MATERNAL IMMUNE FUNCTION AND CONCURRENT ESCHERICHIA COLI INTRAMAMMARY INFECTION DYNAMICS.

Degree: PhD, Veterinary Medicine, 2017, Cornell University

URL: http://hdl.handle.net/1813/47803

► Cows are susceptible to new Escherichia coli intramammary infections (IMI) in the non-lactating period of late gestation (known as the ‘dry period’). These IMI often… (more)

▼ Cows are susceptible to new Escherichia coli intramammary infections (IMI) in the non-lactating period of late gestation (known as the ‘dry period’). These IMI often persist up until parturition without inducing highly inflammatory responses and increase the risk of postpartum mastitis in the subsequent lactation. The bovine maternal immune system is hypothesized to be regulated during late gestation to prevent highly inflammatory, cell-mediated responses however the mechanisms in generating such tolerance have not been fully elucidated. In other mammalian species mononuclear phagocytes play a primary role in generating maternal immune tolerance, and although beneficial for the fetus, often negatively impacts immune responses to invading pathogens. The work presented here investigated changes in maternal immunity and its relationship to dry period E. coli IMI dynamics through the use of experimental and mathematical approaches. The objectives were to 1) characterize changes in blood monocyte composition and monocyte-derived dendritic cell (moDC) function over pregnancy to identify unique changes in late gestation, 2) investigate pregnancy-associated factors that regulate these cells, 3) investigate the relationship between maternal immune regulation and dry period E. coli IMI dynamics and risk of postpartum mastitis through mathematical models, and 4) investigate the effect of intramammary immunization with UV-killed E. coli on IMI dynamics and host response. Pregnancy was accompanied with a decrease in inflammatory monocytes and impaired moDC maturation following E. coli stimulation. Aspects of hindered moDC maturation could be induced by in vitro treatment of late gestation levels of progesterone and estradiol. Deviations in prepartum monocyte composition related to risk of postpartum disease. Mathematical model results indicated these shifts in cytokine production alone were not able to recapitulate IMI dynamics in the dry period, but rather it involved an interaction between maternal immune regulation and physiological and immunological changes to the mammary gland that accompany the dry period. Intramammary immunization at dry-off generated protective responses against E. coli challenge later in the dry period. Overall, shifts in maternal immunity both in the periphery and in the mammary gland during the dry period relate to persistent E. coli IMI and postpartum mastitis, and local immunity can be manipulated to generate protection against IMI in the dry period. Advisors/Committee Members: August, Avery (chair), Schukken, Ynte Hein (chair), Flaminio, Maria Julia Bevilaqua Felippe (committee member), Kanevsky, Isis (committee member), Nydam, Daryl Van (committee member).

Subjects/Keywords: Bovine; E. coli; Late gestation; Mastitis; Monocyte; Monocyte-derived dendritic cell; Veterinary science; Immunology; Epidemiology

…to the exciting world of bovine research when I was an undergraduate at Cornell University…

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APA (6^th Edition):

Pomeroy, B. J. (2017). LATE GESTATION MATERNAL IMMUNE FUNCTION AND CONCURRENT ESCHERICHIA COLI INTRAMAMMARY INFECTION DYNAMICS. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/47803

Chicago Manual of Style (16^th Edition):

Pomeroy, Brianna Joy. “LATE GESTATION MATERNAL IMMUNE FUNCTION AND CONCURRENT ESCHERICHIA COLI INTRAMAMMARY INFECTION DYNAMICS.” 2017. Doctoral Dissertation, Cornell University. Accessed February 28, 2021. http://hdl.handle.net/1813/47803.

MLA Handbook (7^th Edition):

Pomeroy, Brianna Joy. “LATE GESTATION MATERNAL IMMUNE FUNCTION AND CONCURRENT ESCHERICHIA COLI INTRAMAMMARY INFECTION DYNAMICS.” 2017. Web. 28 Feb 2021.

Vancouver:

Pomeroy BJ. LATE GESTATION MATERNAL IMMUNE FUNCTION AND CONCURRENT ESCHERICHIA COLI INTRAMAMMARY INFECTION DYNAMICS. [Internet] [Doctoral dissertation]. Cornell University; 2017. [cited 2021 Feb 28]. Available from: http://hdl.handle.net/1813/47803.

Council of Science Editors:

Pomeroy BJ. LATE GESTATION MATERNAL IMMUNE FUNCTION AND CONCURRENT ESCHERICHIA COLI INTRAMAMMARY INFECTION DYNAMICS. [Doctoral Dissertation]. Cornell University; 2017. Available from: http://hdl.handle.net/1813/47803

Open Access Theses and Dissertations