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Allergic disease encompasses multiple complex syndromes including hayfever, food allergies, eczema and asthma. Atopy is the genetic predisposition towards an IgE-driven immune response in reaction to environmental stimuli, and often serves as a predictor for the development of allergies in the future. While disease etiology is not yet fully understood, many factors including genetics and the environment play a role in the development of allergic disease. Reliable methods for predicting atopic disease development are crucial in emerging therapeutic approaches, which aim to decrease allergic disease severity and clinical progression through early detection and preventative measures. While DCs are emerging as key players in the development of allergic disease, they are challenging to study in vivo due to their low numbers, and ex vivo methods remain relatively unstudied. In this project, receptor expression profiles of atopic-at-risk infants compared to not-atrisk infants were examined in DCs found in cord-blood at birth and CD34+-derived DCs cultured ex vivo. Atopic-at-risks exhibited a higher percentage of ex vivo pDCs expressing TSLPR when compared to not-at-risks. Additionally, an increase of FcεRI expression in atopic-at-risks was found approaching significance in in vivo mDCs. Furthermore, DC differentiation in culture from hematopoietic progenitors and the differences between in vivo and ex vivo DCs were studied. Results indicated a consistent 10-fold increase in the DC population after a 12-day culture compared to cord blood DC numbers. Additionally, a distinct DC population emerged as early as Day 3 with a substantial increase in the percentage of mDCs relative to pDCs. A trend of increased TSLP, CD80, CD86 receptor expression and decreased TLR-5, ST2, FcεRI receptor expression after culture in both mDCs and pDCs was also noted. / Thesis / Master of Science (MSc) / Allergic disease development typically begins in infancy, progressing classically in a series of stages from early life through adulthood. Currently, there is a lack of reliable predictive tests for the development of atopic sensitization and disease. This has slowed efforts to intercept and prevent allergy development at its earliest stages. Dendritic cells (DCs) link innate and adaptive immunity and are thought to be key players in the development of allergic disease. However, the low numbers of DCs in blood make them challenging to study. Methods such as inducing the differentiation of DCs from progenitors are often utilized to obtain a sufficient number of cells. This project investigates whether receptor expression of cord blood-derived DCs grown ex vivo are comparable to the profiles of in vivo DCs at birth. Furthermore, the expression of key receptors on DCs grown in vivo/ex vivo are compared in atopic at-risk, not-at-risk infants.

Staphylococcus aureus causes chronic mastitis in bovines that is difficult to treat with current therapeutics. The goal of this research is to provide information about and improve innate immune responses to infection. Infection can result in host cell apoptosis or programmed cell death. Many pathogens can inhibit apoptosis; thereby acquiring a replicative niche, a reprieve from immune responses, and an escape from treatments. We hypothesize that S. aureus inhibits apoptosis in dendritic cells (DC). To investigate our hypothesis, DC were infected with live S. aureus (LSA), γ-irradiated S. aureus (ISA), or Streptococcus agalactiae (Strep ag.) for 2 hours. Stimulations of DC included ultraviolet light (UV) and lipoteichoic acid (LTA). Results indicate that γ-irradiated S. aureus can inhibit UV-induced apoptosis by upregulating LTA. This research provides information about S. aureus infections, but further research is needed to improve responses to this type of infection. One way to improve innate immune responses to infection is by supplementing bovines with OmniGen-AF®, a probiotic that restores neutrophil function during immunosuppression. To determine the mechanism by which OmniGen-AF® functions, wildtype, MyD88 KO, and TLR4 KO mice were fed either normal chow or supplemented with OmniGen-AF® for two weeks. Mice were immunosuppressed with dexamethasone and challenged with LTA. LTA overcame immunosuppression in a TLR4-depenent manner regardless of supplementation with OmniGen-AF®. Overall this research supplies knowledge about S. aureus inhibition of apoptosis in DC and S. aureus LTA activation of PMN regardless of immunosuppression or supplementation with OmniGen-AF®. / Master of Science

Immune cell niches are microenvironments that support the survival of specific hematopoietic cells. The size of a given niche is dependent on survival and proliferation signals provided. Modulation of niche size can be a useful therapeutic tool, and a better understanding of the factors that control the size of immune cell niches can lead to more targeted therapies. Here bone marrow and thymic niches were modulated with tyrosine kinase inhibition to achieve increased engraftment following stem cell transplantation (SCT). SCT resulting in mixed chimerism is curative for several benign blood diseases, but toxicities associated with myeloablative and cytotoxic conditioning regimens limit the application of SCT. Sunitinib inhibits multiple tyrosine kinases including KIT, an essential survival signal within the hematopoietic stem cell and thymic progenitor niches. Sunitinib therapy diminishes hematopoietic and thymic progenitor cells in mice and enhances accessibility of marrow and thymic niches to transplanted bone marrow. This provides a novel, non-cytotoxic approach to accomplish mixed hematopoietic chimerism. The observation that T cells undergo increased proliferation and accumulate in IL-7R deficient mice compared to other lymphopenic hosts raised questions about the factors that control the size of the T cell niche. Understanding these factors is useful in designing therapeutics to increase T cell responses for treatment of many diseases including cancer. Dendritic cells (DCs) are well known for their ability to modulate T cell responses; however, very little is known about the role of IL-7R signaling on DCs. The data presented here show that bone marrow derived DCs treated with IL-7 were less able to induce T cell proliferation in coculture. In vivo systems using CD11cDTR mice showed a role for IL-7 signaling on CD11c+ cells in T cell homeostasis. Together these data suggest that IL-7R signaling on DCs is important for regulating the size of the T cell niche.

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