12 research outputs found
Dissecting the inflammatory response in melanoma
While the immune system can control tumour growth, regulatory mechanisms, necessary in preventing immunopathology & autoimmunity, contribute to tumour progression impeding elimination of immunogenic tumours such as melanoma. To identify how the inflammatory response can influence tumour biology & be targeted in immunotherapy it is necessary to understand how expression of inflammatory molecules involved in regulatory mechanisms is controlled, which aspects of the inflammatory response are associated with accumulation of immune-regulatory populations & how these impact on frequency & activity of cells involved in tumour control. Tumour-associated macrophages & regulatory T cells possess key tumour-promoting functions, including production of the suppressive cytokine, interleukin 10 (IL-10). I have analysed IL-10 regulation in myeloid cells by disrupting a putative enhancer. The tumour inflammatory environment can influence neutrophil biology, leading to accumulation of low-density granulocytes, suggested to have immunosuppressive functions. I investigated the nature & frequency of low-density granulocytes in melanoma & their correlation with the inflammatory response & disease outcome. I identified low-density cells with an activated phenotype & cells with an immature phenotype enriched in the peripheral blood of stage IV melanoma patients. Marked inter-patient variation in the frequency of these subsets that correlated with accumulation of distinct cytokines, suggested the existence of distinct inflammatory axes. Analysis of patients undergoing anti-CTLA-4 treatment revealed that a lower frequency of activated neutrophils before treatment & an increase in frequency during treatment were associated with better response to anti-CTLA-4. To establish whether accumulation of distinct neutrophil subsets was linked to wider inflammatory changes, the frequency of other immune cell subsets was determined. An enrichment of immature neutrophils was associated with TH2 cell enrichment, whereas an enrichment of activated neutrophils associated with inflammatory monocytes & activated TCR-γδ T cells, further supporting the existence of distinct inflammatory axes. The frequency of activated neutrophils negatively correlated with CCR4+ CXCR3+ CD8+ effector memory T cells, perhaps reflecting greater tumour infiltration of this population. Given the association of this subset with a neutrophil population linked to anti-CTLA-4 response, the importance of CD8+ T cells in anti-tumour responses, & the fact this population had not previously been described, I attempted further characterisation, as well as characterisation of intratumoural CD8+ T cells.</p
Autosomal Recessive Polycystic Kidney Disease: Characterization of Human Peritoneal and Cystic Kidney Cells In vitro
Urinary tract malakoplakia with extension into the retroperitoneum with secondary gastrointestinal involvement
Comparing grazing on lake seston by Dreissena and Daphnia: lessons for biomanipulation
Biomanipulation measures in lakes, taken to diminish algal blooms, have mainly been restricted to the reduction of zooplanktivorous fish with the aim to stimulate the grazing pressure by native filter feeders such as Daphnia. However, larger filter feeders like the exotic zebra mussel, Dreissena polymorpha, have been suggested as an optional tool because of their high filtering capacity. We compared grazing by two filter feeders, D. polymorpha and Daphnia galeata, offered seston from Lake IJsselmeer, the Netherlands in two consecutive years: 2002 and 2003. The seston in both years was dominated by the colony-forming cyanobacterium Microcystis aeruginosa. The grazing studies were performed under controlled conditions in the laboratory and samples were analyzed on a flow cytometer, making it possible to quantify grazing on different seston components and size fractions, including cyanobacteria, other phytoplankton (green algae, diatoms, etc.), and detritus. No differences in clearance rates, on a per weight basis, were found between the two grazer species. The clearance rate on cyanobacteria (especially <20 µm) was lower in 2003 than in 2002. In 2003, the microcystin concentration of cyanobacteria was higher than in 2002, suggesting that the observed lower clearance rate in 2003 was due to the enhanced toxin content of the cyanobacteria. Zebra mussels, although indiscriminately filtering all seston groups out of the water, positively selected for phytoplankton in their mantle cavity, irrespective of its toxicity, and rejected detritus. Since no differences in clearance rates were found between the two grazer species, we conclude that for biomanipulation purposes of shallow lakes, native species like the daphnids should be preferred over exotic species like zebra mussels. When the seston is dominated by phytoplankton that cannot be filtered out of the water column by Daphnia, however, the use of zebra mussels may be considered. Care should be taken, however, in the choice of the lakes since the mussels may have severe ecological and economic impacts.