Friday 10rd August 12noon-12:50pm AM101 Speakers: John Gibbins and Christina Roberts
John Gibbins 2 ½ years into PhD
Supervisors: Ian Hermans and Troels Petersen (The Malaghan Institute of Medical Research) Title: CD8+ Langerin+ Dendritic Cells Activate and Maintain CD8 T Cell Populations After Adoptive Transfer
Adoptive cell transfer (ACT) is a promising new area of anti-cancer therapy. The process involves the isolation of cancer-specific T cells from the patient’s blood, in vitro stimulation and re-infusion of the activated cells back into the patient. This provides a population of effector CD8 T cells capable of a recognizing and killing cancer cells. ACT is currently limited by the ability of these cells to survive in high numbers for an extended period of time and overcoming this problem is therefore a focus to improve the efficacy of the treatment. The activation of cancer-specific CD8 T cells is dependent on the ability of dendritic cells (DCs) to acquire and present exogenous antigens to CD8 T cells, a process known as cross-presentation. We have previously found, a subset of splenic DCs, expressing the CD8 homodimer and the c-type lectin receptor langerin (CD207) have a high capacity for activating CD8 T cells by cross-presentation. This DC subset is found in the marginal zone of the spleen, is highly efficient at phagocytosing apoptotic cells from the blood, and is believed to play an important role in scanning the blood for antigens. We therefore hypothesized the CD8+ langerin+ DCs could influence the survival and population expansion of transferred cancer specific CD8 T cells in the blood. To address the role of the CD8+ langerin+ DCs in activating and maintaining the CD8 T cell population after ACT, we used langerin-diphtheria toxin receptor mice, in which all langerin-expressing cells are depleted in vivo upon injection of diphtheria toxin. For this purpose, we challenged mice intravenously with the T cell thymoma EG7.OVA, and adoptively transferred either naïve or in vitro activated OVA-specific CD8 T cells (OT-I T cells) with or without prior langerin-DC ablation. We found increased numbers of transferred OT-I T cells, in both the naïve and activated settings, when these were transferred into EG7.OVA bearing hosts compared to mice without tumours. Interestingly, this increase was dependent on the presence of CD8+ langerin+ DCs.
Our data therefore suggest that the CD8+ langerin DCs efficiently cross-present antigens within the blood and by this means stimulate the activation of naïve T cells and maintain populations of effector T cells following ACT. Manipulating this DC subset may be an effective way to increase the efficacy of ACT therapy.
Christina Roberts 2nd year of PhD Supervisors: Paul Atkinson and David Maass Title: Study of the Origin of Naturally-Occurring Pharmacogenetic Differences in Yeast Isolates Individuals vary in terms of efficacy and adverse reactions to drugs, which poses a significant healthcare problem (for example, in the case of statins for treatment of atherosclerosis). Variability has both environmental and genetic basis. In a constant environment, differences arise from allelic variation of drug targets or from the numbers of genes involved in complex phenotypes. Traditional drug development programs typically focus on developing drugs for a major gene target. However, most traits, including drug susceptibility, are not controlled by a single gene, but rather arise from an interacting network of multiple loci. The aim of this PhD project is to investigate the genetic basis for naturally-occurring susceptibility differences to three drugs—atorvastatin (a cholesterol-lowering agent), benomyl (a microtubule-destabilising drug), and ketoconazole (a fungicide that inhibits ergosterol biosynthesis). We have used 34 natural strains of the budding yeast Saccharomyces cerevisiae for this purpose. These strains, originating from the Sanger Institute, are of different genetic backgrounds, and of known sequence. They have similar levels of single nucleotide polymorphism variation as human individuals, and we therefore plan to use them as a model of individuals’ differences in drug response. We have determined that these strains display a range of susceptibility profiles to our drugs of interest that are not explained by differences in target sequences. Our goal is to use the genetic mapping technique of quantitative trait locus analysis and sequence analysis, to identify the loci and networks responsible for drug resistance.
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