No description available.

The scientific method requires the creation of a unifying hypothesis that reconciles an observed health outcome of infection with experimental data gathered about the disease process following infection. In this era of unprecedented amounts of data and information for various disease models, the creation and articulation of such hypothesis are often beyond human capacity. Modeling offers a means to generate hypothesis that provide complex mechanisms that reconcile seemingly contradictory data as well as quantitatively assess the relative plausibility of different mechanisms proposed to explain the same data/health outcome association. Here I explain the modeling approach to hypothesis generation and offer several examples of its implementation to address the role of the natural host immune response in determining outcomes of infection by a specific microbe including pathogenesis and microbial clearance. Such knowledge is key to devising sophisticated disease intervention strategies. The systems studied are i) Inflammatory Bowel Disease, where I explore mechanisms of inflammation regulation and how they break down to give rise to a chronic inflammatory disease, ii)H. pylori infection, in which I explore potential bacterial strategies for persistence as a commensal of the microflora or as a pathogen, and iii) HIV infection, where I explore the role of inflammatory and anti-inflammatory mechanisms in establishing viral infection. I present both mathematical, equation based models as well as agent-based, computational models offering a comparison of each method. / Ph. D.

Infection with Epstein-Barr virus (EBV) during adolescence results in an immunopathological disease, Infectious Mononucleosis (IM), in around 25% of cases. A role for Regulatory T cells (Treg) in IM has yet to be established. These suppressive cells may affect the well-characterised cytotoxic T cell (CTL) response to EBV and thus the level of viral persistence and reactivation, potentially creating an environment conducive to the outgrowth of EBV-infected cells and tumour development. The work in this thesis examines the frequency and functional capacity of Treg in primary EBV infection. The results show that the frequency of Treg within the CD4+ T cell population of IM patients was reduced with borderline significance (p=0.05) compared with healthy controls as revealed by fluorescence activated cell sorting. Treg function was confirmed using suppression assays on peripheral blood mononuclear cells (PBMC) from healthy controls but could not be assessed in IM patients due to low cell numbers. EBV-specific Treg function was analysed using Interferon (IFN)-γ ELISPOT assays in which PBMC from IM patients and healthy controls were stimulated with phytohaemagglutinin (PHA) and EBV peptides in the presence or absence of Treg. The IFN-gamma response of PBMC to PHA stimulation was significantly reduced in IM patients compared to healthy controls (p=0.009) but the IFN-gamma response to EBV peptides did not alter, irrespective of the presence or absence of Treg. Investigation of FOXP3 expression by immunohistochemistry provided evidence of Treg presence and preliminary data indicated an increased expression in IM tonsil sections compared with healthy tonsil sections. The proliferative responses and cytokine profiles of healthy controls, as measured by proliferation assays and ELISAs, in response to stimulation with the recall antigen PPD did not significantly alter upon the addition of latent membrane protein (LMP)-1 peptide. In IM patients, the same treatment resulted in a significant reduction in IFN-gamma (p=0.026) but no significant differences in IL-10 production or cell proliferation. The significantly reduced frequency of Treg in peripheral blood of IM patients and abundant FOXP3 expression in IM tonsils provides evidence for a Treg role in primary EBV infection. One plausible explanation is the recruitment of Treg to the site of primary infection by an as yet unidentified EBV-specific mechanism. Clarification of Treg activity in IM may expose opportunities for immunomanipulation during early stages of infection.

Thesis (Ph.D.)--University of California, San Francisco, 2004. / Bibliography: leaves xxx-xxx. Also available online.

Thesis (Ph.D.) - University of Queensland, 2006. / Includes bibliography.

No description available.

Milk protein has been implicated as a factor in the development of atherosclerosis. Significantly higher titers of antibodies (P < 0.0002) toward milk antigens were observed in patients suffering from coronary heart disease as compared to age matched controls. These hemagglutination titers were not sex related but may have been related to age. Specificity of the antigen-antibody reaction was demonstrated by a hemagglutination inhibition test. The complement fixation test was evaluated and was less sensitive than the tanned hemaggIutination test. Treatment with 2-mercapto-ethanol resulted in reduced hemagglutination titers, indicating that significant antibody activity may be due to IgM. A special application of the Combs test detected specific antibodies on the surface of tanned and coated RBC which did not otherwise produce detectable agglutination.

<p>Prenatal life events have been long observed to be able to influence disease into adulthood in both epidemiological and animal studies. Prenatal stress (maternal stress during gestation) is one of such factors that has been shown to impact cognition and behaviour of the offspring. However, the effects of prenatal stress on the immune system are not understood. This study has evaluated the effects of prenatal stress on a murine model. Prenatal stress increased allergic airway inflammation in male, but not female offspring following sensitization and challenge with cockroach extract. This corresponded with stress-induced changes in the immune environment of non-sensitized animals. These changes included a decrease in regulatory T cells at baseline in males compared to non-stressed controls and increased splenic dendritic cell percentage and cytokine, particularly IFN-γ, secretion compared to prenatally stressed females. In females, prenatal stress decreased allergic inflammation, which corresponded to a decreased percentage of dendritic cells in the lung and mesenteric lymph node. Prenatal stress did not affect dendritic cell antigen presentation in ether male or female offspring. There was no evidence to suggest a prenatal stress induced change in glucocorticoid sensitivity of dendritic cells. In order to explore the possibility of prenatal stress induced decrease of parasympathetic output, a vagotomy model was used as a proof of concept in naïve animals not exposed to prenatal stress. Vagal modulation of dendritic cell phenotype and function was assessed. While there was some evidence that vagotomy may indirectly modulate dendritic cell function, its effects on the immune system were different then the changes caused by prenatal stress and thus it is a role of reduced parasympathetic output was not supported. Overall this data indicates a role of prenatal stress on the immune system with clear sex differences, but the mechanism for how this occurs is currently unknown. Further research is needed to investigate the role of TLRs and IFN-γ in this model, as well as other possible mediators of prenatal stress such as the changes to the parasympathetic nervous system that may in turn mediate alterations to the immune system. Differences in when the effects of prenatal stress are expressed during postnatal life are discussed.</p> / Master of Science (MSc)

<p>Influenza is a highly contagious respiratory disease. Yearly epidemics and pandemics account for high morbidity and mortality worldwide. Lung immunopathology is a major factor causing death following influenza. In addition, secondary bacterial superinfections that occur after influenza further complicate the lung immunopathology and contribute to higher morbidity and mortality. The research presented in this thesis addressed important, understudied questions in the complicated field of tissue immunopathogenesis and host defense to influenza and pneumococcal infections. Firstly, in a model of acute respiratory influenza infection, we found that the classically proinflammatory cytokine TNF plays a dual and biphasic role at different times post-infection. While it does have pro-immune roles in the beginning stages, TNF acts as a negative type 1 immune regulator at later points of infection. TNF controls the level of immune activation and has a key role in preventing lung immunopathology and aberrant tissue remodeling. Secondly, to further investigate mechanisms of lung pathology, we elucidated the role of bacterial replication and over activated host immune responses during bacterial superinfection following influenza. In our model of pulmonary <em>Streptococcus pneumoniae</em> infection after influenza, we found that dual infected animals experience rapid weight loss and succumb to infection. Bacterial outgrowth, dysregulated cytokine and chemokine expression, and severe lung neutrophilia and immunopathology are linked to the poor clinical outcome. Combined treatment with both an antibiotic azithromycin and corticosteroid dexamethasone best improves clinical outcome, bacterial clearance, cellular and cytokine responses, and immunopathology. Thirdly, in our continuing interest for improved therapies during pulmonary infections, we tested the transgenic expression of type I IFN as a treatment during <em>S. pneumoniae</em> infection. We found that IFN-a controls bacterial outgrowth and improves clinical outcome. Together, our findings provide novel insights into the mechanisms of lung immunopathology and treatment protocols for pulmonary influenza and pneumococcal infections.</p> / Doctor of Philosophy (Medical Science)

Type 2 (TH2) immune responses evolved to respond to helminth parasite infections by the production of TH2 cytokines, which stimulate anti-helminth immunity. Macrophage migration inhibitor factor (MIF) is a pleiotropic cytokine, which is produced by many cell types. We demonstrate that mice deficient in MIF have enhanced clearance of a helminth parasite. MIF deficiency in CD4+ T cells was found to be the most important for mediating parasite clearance. We mimicked MIF deficiency by administering an inhibitor of the MIF tautomerase activity, sulforaphane, and this also increased parasite clearance (Section I). TH2 immune responses underlie allergy and allergic asthma, in which the same cytokines that help expel parasites are released in response to innocuous substances. Integral to the initiation of adaptive TH2 immunity are dendritic cells (DCs), which take up antigen and stimulate antigen-specific CD4+ T cell responses. We found that DC expression of ADAM10, a zinc-dependent metalloproteinase, is critical for the development of TH2 immune responses and IgE production from B cells. This effect is demonstrated in both allergic airway inflammation and anaphylaxis models. ADAM10-deficient DCs are unable to cleave Notch1 receptors, resulting in reduced IL-6 production and this ultimately results in decreased TH2 activity. ADAM17 is closely related to ADAM10 in both structure and function. Interestingly, mice from which ADAM10 and 17 are removed from DCs (ADAM10/17DC-/-) have a distinct phenotype from both ADAM10DC-/- and ADAM17DC-/- mice in models of allergic airway inflammation (Section I). We also examined another effect of TH2 cytokines on the interaction between mast cells and myeloid derived suppressor cells (MDSCs). We sought to understand how histamine and IL-13, mediators made by mast cells, affect the immunoregulatory function of MDSCs. MDSCs in IL-13-deficient mice with tumor are more prevalent in circulation rather than in tumor or organs, which could be due to changes in CCL2/CCR2 chemotaxis. In addition, MDSC function after treatment with the DNA methyltransferase inhibitor, decitabine was examined. This treatment reduced their suppressive function and increased the expression of molecules needed for antigen presentation. Overall, TH2 immunity has multifaceted roles in anti-parasite immunity, allergic asthma, and MDSC function (Section II).