Modelling CLL cell and T-cell Migration in a Dynamic Circulating Model of CLL
Poster Apr 21, 2015
Elisabeth Walsbyl, Paul Brennan', Guy Pratte, Andrea Buggins3, Tanja N Hartmann'', Chris Fegan1 and Chris Pepper'
We have recently developed a novel circulating model of chronic lymphocytic leukaemia (CLL) that mimics the transient interactions that take place between circulating lymphocytes and vascular endothelium. Here we show that both normal and malignant lymphocytes actively underwent transendothelial migration. Furthermore, seeding of CXCL12-secreting MRC5 cells into the extravascular space (EVS) resulting in significantly enhanced CLL cell migration (P = 0.024) but no increase in T-cell migration. Both CLL cells and T-cells recovered from the EVS showed evidence of activation markers and entry into cell cycle as demonstrated by increased Ki-67 expression (P<0.0001). We subsequently established that CLL cell Ki-67 expression was dependent on the presence of T-cells, as depletion of the T-cells from the circulating compartment significantly inhibited Ki-67 induction (P = 0.003). It is worthy of note that as a proportion of all circulating peripheral blood mononuclear cells, CD3+ T-cells migrated significantly more than CD19+ CLL cells (P = 0.02). This seems likely to be promoted by CLL cell secretion of T-cell attracting chemokines CCL3 (298pg/m1±197.5) and CCL4 (56pg/m1±115.6) in our model. Interestingly, CD38+ CLL samples showed elevated levels of CCL3 and CCL4 suggesting that increased T-cell recruitment may contribute to the inferior clinical outcomes seen in these patients. Taken together the data presented here highlight the requirement of T-cells in the pathology of CLL.
Characterization of a Type 2 diabetes-associated islet-specific enhancer cluster in STARD10 by genome editing of EndoC-βH1 cellsPoster
Genome-wide association studies (GWAS) have identified more than 100 genetic loci associated with type 2 diabetes. The majority of these are located in the intergenic or intragenic regions suggesting that the implicated variants may alter chromatin conformation. This, in turn, is likely to influence the expression of nearby or more remotely located genes to alter beta cell function. At present, however, detailed molecular and functional analyses are still lacking for most of these variants. We recently analysed one of these loci and mapped five causal variants in an islet-specific enhancer cluster within the STARD10 gene locus. Here, we aimed to understand how these causal variants influence b-cell function by alteration of the chromatin structure of enhancer clusterREAD MORE
P450 Induction in Cryopreserved Hepatocytes from PXR and CAR Nuclear Receptor Knock-out RatsPoster
The nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are closely related transcription factors that regulate the expression of phase I (cytochrome P450s), phase II metabolizing enzymes and transporter genes in response to xenobiotics, including prescription drugs.READ MORE
Treatment Options for Chronic Parvovirus Viremia in Pediatric Heart Transplant Patients in a Tertiary Care CenterPoster
This abstract discusses three cases of pediatric heart transplant patients who suffered from parvovirus (B19) infection. Of these patients, two ( B & C) responded well to standard intravenous Ig therapy. Patient A however, did not respond to standard treatment and was begun on subcutaneous Ig, which effectively diminished his viral load. Thus, subcutaneous Ig infusions might serve as a second line treatment for transplant patients with parvovirus who do not respond well to the standard approach.READ MORE