"February 1977." Includes bibliographical references (leaves [105]-[120]) The malignant transformation, and the relevance of developmental antigens to the cancer process, is broadly reviewed. The two developmental antigens - foetal and placental - are then examined in experimental mouse and rat tumour systems.

"February 1977." / Includes bibliographical references (leaves [105]-[120]) / xiv, 104, [16] leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / The malignant transformation, and the relevance of developmental antigens to the cancer process, is broadly reviewed. The two developmental antigens - foetal and placental - are then examined in experimental mouse and rat tumour systems. / Thesis (Ph.D.)--University of Adelaide, Dept. of Animal Physiology, 1978

Copy of author's previously published work inserted. Bibliography: leaves 139-160.

Copy of author's previously published work inserted. / Bibliography: leaves 139-160. / 160, [10] leaves, [41] leaves of plates : ill. (chiefly col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Molecular Biosciences, 2001?

Mycobacterium tuberculosis (M. tuberculosis) , the etiological agent of tuberculosis, is an intracellular bacterium which persists within macrophages. Successful control of tuberculosis depends on T-cell-mediated immunity. Immune protection involves the development of a Th1 response characterised by the secretion of cytokines such as IL-12, IFN-γ and TNF-α. The progression towards disease in humans and mice is often associated with a Th2 response characterised by the secretion of cytokines such as I L-4 and I L-10. Mycolic acids, the major cell wall lipid of M. tuberculosis, were previously shown to have a marginally protective effect on the development of disease in Balb/c mice when administered intravenously at an optimal dose of 25 µg one week before intravenous M. tuberculosis infection. Here it is shown that the protective effect is highly significant when infection is done intranasally. The protective effect of 25 µg mycolic acids against tuberculosis could not be explained by induction of a longer lasting Th1 response in Balb/c mice. This was determined by using semi-quantitative RT-PCR on the mRNA of cytokines characteristic of the different immune responses. It was observed that maximum sensitivity was obtained at the lowest possible PCR cycle and template concentrations for the samples. Mycolic acids were the first non-protein antigens shown to induce an immune response after presentation on CD1 membrane proteins. Balb/c mice predominantly generate a Th1 response during the first 3 - 4 weeks of M. tuberculosis infection, whereas they generate a Th2 response in the following weeks. Even though the protective effect of 25 µg mycolic acids could not be associated with a prolonged Th1 immune response in infected mice, it did induce IL-12 and IL-10 mRNA in uninfected mice. These cytokines are primarily. / Dissertation (MSc (Biochemistry))--University of Pretoria, 2005. / Biochemistry / unrestricted

[Truncated abstract] The design and development of effective anti-viral immunotherapies requires a comprehensive understanding of the cellular and molecular processes that are involved in the generation and regulation of immune responses. The fundamental objective of the immune system is to successfully complete the task of eliminating/controlling the invading pathogen without causing overt pathology. Cytomegaloviruses (CMVs) are large DNA viruses that are able to evade immune attack and persist lifelong within the host. In a healthy host, CMV causes an asymptomatic infection, but in instances of decreased immune functions, such as in newborns, acquired immunodeficiency syndrome (AIDS) patients and transplant recipients, the infection can result in serious morbidity and mortality. Thus, human CMV (HCMV) is a clinically important pathogen and an understanding of the pathogenesis, mechanisms of immune subversion and, importantly the cascade of immune events that ensue following infection is highly relevant. The studies presented in this thesis have provided useful insight into various aspects of viral immunity and it is hoped that they will assist in the design of more effective therapies against viruses of clinical importance. Genetic variability in humans can greatly influence anti-viral immune responses and the outcome of viral infection. ... Furthermore, these studies provide novel evidence that NK cells are also crucial for the control of virus in some organs of susceptible mice during early acute infection. The data reveals that both NK cells and CD8+ T cells utilise perforin- and IFN-? dependent control of MCMV. Furthermore, these studies provide novel evidence that protection mediated by Ly49H+ NK cells in resistant mice is dependent on perforin. Chapter 3 focuses on the biological relevance of Grz during MCMV infection. These studies found that GrzA and GrzB are essential components of the machinery involved in limiting MCMV during acute infection. These analyses also provide the first evidence suggesting that GrzM plays a role, albeit minor, in controlling MCMV replication. Furthermore, the current studies suggest that Grz can mediate direct antiviral activities independent of the induction of cell death in conjunction with perforin. Interestingly, in the absence of both GrzA and GrzB (GrzAB), mice were as susceptible to MCMV infection as perforin-deficient mice. However, unlike perforin-deficient mice, GrzAB-deficient mice controlled and survived the infection. In Chapter 4 the roles of perforin, GrzA and GrzB in anti-viral immunity and immunopathology during MCMV infection were examined. These studies show that NK cell-derived perforin is required to eliminate infected targets as well as activated effector cells, suggesting that NK cells are crucial not only in defensive immunity but also in limiting the immune activation that follows MCMV infection. In summary, the studies presented in this thesis define the significant role played by specific effector molecules in limiting MCMV replication during different stages of this viral infection. Furthermore, these studies provide novel evidence that perforin, GrzA and GrzB play distinct roles in defensive immunity and limiting immunopathology during MCMV infection.

Cytomegalovirus (CMV) is a ubiquitous pathogen affecting over 95% of the world’s population. While infection is typically asymptomatic in healthy individuals, the virus persists life-long in its host and can be reactivated following withdrawal of immune control. As such, it remains a serious clinical concern in individuals who are immunocompromised, such as newborns and neonates, transplant and/or chemotherapy recipients, and HIV/AIDS patients. CMV also has the ability to cause immunosuppression, the mechanisms of which include defective antigen presentation to T cells and interference with haematopoiesis in the bone marrow (BM). Due to strict species specificity, murine CMV (MCMV) provides a relevant model for the study of CMV modulation of the immune system in vivo in its natural host. The type I interferons (IFNs) represent a major family of cytokines involved in the early response to MCMV infection. Their anti-viral activity and regulation of NK cell activation and cytotoxicity are of significant interest in the context of MCMV infection, as genetic resistance to MCMV is mediated by the ability of Ly49H+ NK cells to directly recognise and lyse infected cells. Chapter 2 comprises an analysis of acute MCMV infection in the absence of type I IFN activity. These studies were conducted in IFNAR1 and IFNAR2 deficient mice, which lack components of the type I IFN receptor. Data obtained from these studies confirmed the essential requirement for type I IFN in controlling viral titres, promoting expansion of splenic Ly49H+ NK cells, and inducing early activation of NK cell cytotoxicity. In addition, our data depicted an accumulation of infected myeloid cells in the absence of effective NK cell-mediated control. This was paralleled by a significant increase in the level of serum TNF-a and IFN-¿, an effect which in some cases has been linked to serious pathological disease. Thus, the data described in this chapter provide an insight into the consequences arising from delayed NK cell responses to MCMV infection in the absence of type I IFN. vii Type I IFN can also potentially affect BM haematopoiesis. BM atrophy and impairment of myelopoiesis are serious consequences of CMV infection. During acute MCMV infection we consistently observed a profound loss of splenic dendritic cells (DCs) in BALB/c mice. Since all DC subsets are derived from BM haematopoietic progenitor cells, the possibility that MCMV might interfere with BM haematopoiesis and DC differentiation was explored. Chapters 3 and 4 describe the impact of acute MCMV infection on BM progenitors, with particular emphasis on the differentiation capabilities of these cells in ex vivo culture systems. Chapter 3 focuses on the effect of MCMV infection on BM cellularity and frequency of specific BM progenitor populations. A thorough analysis of contributing factors, such as viral infection of BM cells, involvement of type I and II IFNs, progenitor cell trafficking and NK cell activity in the BM compartment, was conducted. Our results showed that a severe loss of BM cellularity occurs in MCMV-infected mice. Furthermore, when BM cells from MCMV-infected mice were cultured ex vivo in granulocyte macrophage-colony stimulating factor (GM-CSF), there was an impairment in their ability to differentiate into DCs.

Cytomegaloviruses (CMVs) are ubiquitous in nature, having evolved over many millenia with their hosts. While in healthy hosts most infections with CMV are asymptomatic, the virus can cause severe disease in immunocompromised hosts. Thus, the increase in organ transplantation and the HIV/AIDS pandemic have established human CMV (HCMV) as a clinically important pathogen. Indeed, HCMV infections are now the major cause of morbidity and mortality among immunocompromised patients, which has led to more research targeting CMV for effective anti-viral treatment. The discovery that cytomegaloviruses encode several genes which are involved in immune escape has prompted a new area of research, aimed at understanding immune escape mechanisms for exploitation as potential anti-viral therapeutics. By targeting the viral proteins directly, or their receptors in the host, it may be possible to treat CMV disease by agonistic/antagonistic therapy. The first part of this thesis describes the first demonstration of anti-NK1.1 staining in situ to identify NK cells using a modified in vivo perfusion/fixation method. Using this method, we have compared the acute NK1.1+ cellular response to wild-type MCMV infection in the visceral organs of genetically susceptible intra-NK complex recombinant BALB.B6-CT6 (Cmv1s, NK1.1+) mice with resistant C57B⁄J (Cmv1r, NK1.1+) and BALB.B6-Cmv1r mice (Cmv1r, NK1.1+). Expression of viral antigens and the consequences of infection on other cellular subsets, were also analyzed in this study. The data show that in susceptible mice (Cmv1s) MCMV infection is predominent in the marginal zone of splenic white pulp, resulting in local changes in various cellular constituents, including macrophages, NK cells and DC. In the liver, distinct foci of infection were comprised of large numbers of macrophages and NK1.1+ cells surrounding infected cytomegalic cells. In resistant mice (Cmv1r), 6 MCMV infection predominantly affected the red-pulp of the spleen and was associated with increased accumulation of NK1.1+ cells and macrophages at sites of viral infection