Clinical Pathology - Theses
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ItemViral and host inflammation and host immunity in the pathogenesis and therapy of tumours caused by Kaposi Sarcoma herpesvirus( 2018)Kaposi sarcoma associated herpesvirus (KSHV), also known as human herpesvirus-8, is the aetiological agent of three tumours: Kaposi sarcoma, a form of multicentric Castleman disease (KSHV-MCD), and primary effusion lymphoma (PEL). These tumours are predominantly seen in people with acquired immunodeficiencies, including HIV. The burden of KSHV-associated tumours is particularly significant in resource-limited settings including Africa. Current therapies are limited by an incomplete understanding of disease pathogenesis, in particular the role of inflammation and impaired immunity in tumorigenesis. This work examines the inflammatory pathogenesis and associated clinical characteristics of KSHV-MCD, showing for the first time that virally encoded and human cytokines, viral and human IL-6, cooperate in disease activity and have an independent effect on clinical features. It then demonstrates the role of functional imaging in patients with KSHV-MCD, showing a distinctive pattern of 18FDG-PET changes associated with disease activity and severity, and further illuminating pathogenesis by demonstrating that the underlying abnormalities are systemic. These findings are used as the basis for a prospective exploration of a novel syndrome of KSHV-associated inflammation distinct from KSHV-MCD, the KSHV-inflammatory cytokine syndrome, defining for the first time its clinical, imaging, virological and immunological parameters in relation to KSHV-MCD and HIV. Finally, integrating this understanding of the pathogenic role of immunity and inflammation, a prospective interventional evaluation of an oral immune modulator, pomalidomide, as therapy of symptomatic KS is explored. This shows that this agent is well tolerated, with an overall response rate of 73% (95% CI 50-89%), and correlative studies explore its impact on underlying immune dysfunction. Taken together, these results have a significant impact on our understanding of KSHV-associated tumours. They have implications for rational therapy development, including approaches applicable in resource-limited setting and therapies tailored to the inflammatory manifestations and immune predispositions that have emerged as characteristic of these tumours.