Thesis (M.D. 1974) from the Dept. of Medicine, University of Adelaide.

Thesis (Ph. D.)--University of Sydney, 2006. / Title from title screen (viewed 21 May 2007). Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the School of Public Health, Faculty of Medicine. Includes bibliographical references. Also available in print form.

Many causes of esophagitis exist in immunocompromised patients. Uncommon pathogens must be considered to facilitate timely and appropriate therapy. A limited number of cases of esophageal actinomycosis have been reported. This report describes an unusual case of esophageal actinomycosis in a patient with persistent dysphagia. The broad differential may have delayed definitive diagnosis in the case study patient. Biopsy and culture are essential for accurate diagnosis. Although actinomycosis is a rare disease, it should be included in the differential diagnosis of patients presenting with oral or esophageal complaints. It may also be considered as an opportunistic infection in immunocompromised patients. The treatment of choice is parenteral penicillin G, 18 to 24 million units for 2 to 6 weeks followed by oral therapy for 6-12 months.

A functional immune system is a potential barrier to tumor growth and progression. Cancer is caused, in part, by the loss of immune surveillance leading to the inability of the immune system to destroy the cancer cells. Macrophages (Mfs) are essential cellular components of the immune system; they influence immune responses in diverse and fundamental ways. As a consequence, Mfs present targets for tumors to evade, thereby enhancing tumor survival and growth. An interaction between CD40 on Mfs and CD40L on T cells is required for cell-mediated inflammatory responses. The CD40/CD40L interaction is bi-directional; suppressed expression of either protein by the tumor will prevent activation of both Mfs and T cells. We showed that tumor growth suppresses T-cell CD40L expression. Decreased CD40L expression disrupted Mf activation pathways, leading to impaired production of immunostimulatory cytokines, interleukin (IL)-12 and IL-18 by tumor-bearing host (TBH) Mfs. Disruption of CD40L expression, via dysregulation of IL-12 and IL-18 production, impeded T-cell interferon (IFN)-g production, which in turn exacerbated Mf dysfunction. We showed that IFN-g induced interferon consensus sequence binding protein (ICSBP) expression is impaired in TBH Mfs due to tumor cell-derived TGF-b and, to a lesser extent, IL-10. ICSBP induces CD40L, IL-12, and IL-18 expression. Disruption of the CD40/CD40L interaction via lowered CD40L expression generates an immunosuppressive loop that may be a strategy for tumor survival and growth. This was demonstrated by impaired cytotoxicity; via impaired tumor necrosis factor (TNF)-a and nitric oxide (NO) production by TBH Mfs against Meth-KDE tumor cells. Collectively, these studies show that multiple antitumor mechanisms could be enhanced by restoration of CD40L expression. / Master of Science

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The leukocyte immunoglobulin like receptors (LILRs) are a group of receptors with immunomodulatory effects. Group 1 LILRs comprise of LILRB1, among others, and bind to class 1 MHC molecules and transmits inhibitory signals. Studies have shown that LILRB1 ligation during the monocyte differentiation process into dendritic cells (DCs) results in the generation of a population of cells that are tolerogenic. Here we hypothesize that this tolerogenic nature of the resultant cells is due to the high expression of nuclear factor kappa – light chain enhancer of activated B cells (NF-κB) inhibitor – A20 binding inhibitor of NF-κB signalling 1 (ABIN1). In this study we analyzed the effect that ABIN1 exerts on the maturation of DCs and CD14+HLA-DRlow/- monocytes - a population of cells that have been recently been identified as myeloid derived suppressor cells (MDSCs) in humans. LILRB1 ligated DCs and CD14+HLA-DRlow/- monocytes, when treated with ABIN1 siRNA, displayed an increase in the expression of antigen presentation and co-stimulatory molecules such as CD80, CD86, HLA-DR and HLA-ABC and displayed a greater capacity to produce cytokines like IL-12 and IFN-α. Additionally, they displayed a greater capacity to stimulate the adaptive component of the immune system in terms of IFN-γ production, cell proliferation and adapter molecule and mitogen activated protein kinase (MAPK) activation in T cells. Based on the results we obtained, it can be concluded that ABIN1 plays a significant role in maintaining the immature and suppressive phenotype of immature myeloid cells (IMCs) by dampening NF-κB signalling, while also exerting a negative effect on antiviral signalling.

[20] 172 [45] leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (M.D. 1974) from the Dept. of Medicine, University of Adelaide