No description available.

<h4> </h4> / <p>Asthma is an inflammatory disorder of the airways, and there has been growing insight into the cellular and molecular mechanisms underlying the inflammatory basis of this disease. Research into the inflammatory mechanisms of asthma has progressively shifted focus from downstream effectors, such as mast cells and eosinophils, up to Th2 lymphocytes and their proallergic cytokines. Even more upstream in the allergic cascade are dendritic cells (DCs), potent APCs that orchestrate immune responses. Evidence supporting a role of DCs in regulating airway allergic inflammation is derived mainly from animal studies. In animal models of asthma, myeloid DCs (mDCs) induce and maintain airway inflammation, while plasmacytoid DCs (pDCs) mediate tolerance and lung homeostasis. It remains uncertain, however, whether this concept of pro-allergic mDCs and anti-allergic pDCs translates from animal to human models. The overall objective of this thesis was to investigate the biology of DC subsets in allergen-induced asthma in asthmatic subjects. Initially, we demonstrate that both mDCs and pDCs increase in the airways of subjects with mild asthma after allergen inhalation. Next, we describe a distinct subpopulation of mDCs, called mDC2s, and demonstrate their association with allergy and asthma severity. Expanding on these findings, we show that mDC2s increase in the airways of mild asthmatics after allergen challenge. Lastly, we explore the potential of pharmacological therapies, anti-OX40L MAb and anti-TSLP MAb, to affect DCs in subjects with mild asthma, and demonstrate no effect of either drug on circulating DC subsets. The studies presented here provide evidence for multiple DC subtypes being involved in the regulation of allergen-induced inflammatory responses, and support continued investigations into the biology of different DC subsets in allergen-induced asthma.</p> / Doctor of Philosophy (Medical Science)

E. coli O157:H7 is the most important serotype of enterohaemorrhagic E. coli (EHEC) which is of concern to public health worldwide. As a common cause of haemorrhagic colitis, EHEC infection can progress to life threatening sequelae including haemolytic uraemic syndrome (HUS) in humans. Human infection rates are higher in Scotland than found in the rest of the UK. Cattle are asymptomatic carriers of EHEC and are an important reservoir from which disease outbreaks can spread. The terminal rectum has been indicated as a site of E. coli O157:H7 colonisation in the bovine intestinal tract. This is the location of numerous lymphoid follicles which contain dendritic cells (DCs) which are professional antigen presenting cells and important directors of immune responses. DCs are likely to come into contact with EHEC and therefore could be key in this location for enabling EHEC to colonise the bovine host. The first aim of this project was to characterise dendritic cells within the bovine intestinal tract at various anatomical locations, including the terminal rectum, using immunohistochemistry techniques. Following this, work to extract and further phenotype dendritic cells from terminal rectal tissues was undertaken. Finally, a widely-used bovine dendritic cell model was employed to generate dendritic cells from circulating blood monocytes. This model was utilised to investigate the interactions of dendritic cells with EHEC strains compared with responses to bovine enterotoxigenic (ETEC) and bovine commensal E. coli strains. Early work identified that there are potentially numerous DCs within the bovine intestinal tissues and these cells were found in greater numbers at the terminal rectum. Protocols to extract and further characterise these cells were developed but proved inconsistent, with large variation between animals. Using the monocyte derived dendritic cells (moDCs), differences were observed between immunological responses to challenge with E. coli O157:H7 strains and bovine pathogenic or commensal E. coli strains. Cytokine production, cell surface molecule expression, cell phenotype and viability as well as intracellular bacterial counts were compared. The data presented here shows that the bovine moDCs respond differently to EHEC strains when compared with commensal or pathogenic E. coli in several key areas. This has important implications for the responses of the bovine host to various E. coli strains. This work also indicates that dendritic cells could be central to these responses and if studied further still, may hold the key to reducing the colonization and persistence of E. coli O157:H7 in cattle, and subsequent human disease outbreaks.

published_or_final_version / abstract / Microbiology / Master / Master of Philosophy

published_or_final_version / abstract / Pathology / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Pathology / Master / Master of Philosophy

published_or_final_version / abstract / Surgery / Doctoral / Doctor of Philosophy

published_or_final_version / Medicine / Master / Master of Philosophy

published_or_final_version / abstract / Pathology / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Pathology / Doctoral / Doctor of Philosophy