4 results found
Reed DM, Paschalaki KE, Starke RD, et al., 2015, An autologous endothelial cell: peripheral blood mononuclear cell assay that detects cytokine storm responses to biologics, The FASEB Journal, Vol: 29, Pages: 2595-2602, ISSN: 0892-6638
There is an urgent unmet need for human tissue bioassays to predict cytokine storm responses to biologics. Current bioassays that detect cytokine storm responses in vitro rely on endothelial cells, usually from umbilical veins or cell lines, cocultured with freshly isolated peripheral blood mononuclear cells (PBMCs) from healthy adult volunteers. These assays therefore comprise cells from 2 separate donors and carry the disadvantage of mismatched tissues and lack the advantage of personalized medicine. Current assays also do not fully delineate mild (such as Campath) and severe (such as TGN1412) cytokine storm‐inducing drugs. Here, we report a novel bioassay where endothelial cells grown from stem cells in the peripheral blood (blood outgrowth endothelial cells) and PBMCs from the same donor can be used to create an autologous coculture bioassay that responds by releasing a plethora of cytokines to authentic TGN1412 but only modestly to Campath and not to control antibodies such as Herceptin, Avastin, and Arzerra. This assay performed better than the traditional mixed donor assay in terms of cytokine release to TGN1412 and, thus, we suggest provides significant advancement and a definitive system by which biologics can be tested and paves the way for personalized medicine.—Reed, D. M., Paschalaki, K. E., Starke, R. D., Mohamed, N. A., Sharp, G., Fox, B., Eastwood, D., Bristow, A., Ball, C., Vessillier, S., Hansel, T. T., Thorpe, S. J., Randi, A. M., Stebbings, R., Mitchell, J. A. An autologous endothelial cell:peripheral blood mononuclear cell assay that detects cytokine storm responses to biologics. FASEB J. 29, 2595‐2602 (2015). www.fasebj.org
Prostacyclin is a powerful cardioprotective hormone released by the endothelium of all blood vessels. Prostacyclin exists in equilibrium with other vasoactive hormones and a disturbance in the balance of these factors leads to cardiovascular disease including pulmonary arterial hypertension. Since it's discovery in the 1970s concerted efforts have been made to make the best therapeutic utility of prostacyclin, particularly in the treatment of pulmonary arterial hypertension. This has centred on working out the detailed pharmacology of prostacyclin and then synthesising new molecules based on its structure that are more stable or more easily tolerated. In addition, newer molecules have been developed that are not analogues of prostacyclin but that target the receptors that prostacyclin activates. Prostacyclin and related drugs have without doubt revolutionised the treatment and management of pulmonary arterial hypertension but are seriously limited by side effects within the systemic circulation. With the dawn of nanomedicine and targeted drug or stem cell delivery systems it will, in the very near future, be possible to make new formulations of prostacyclin that can evade the systemic circulation allowing for safe delivery to the pulmonary vessels. In this way, the full therapeutic potential of prostacyclin can be realised opening the possibility that pulmonary arterial hypertension will become, if not curable, a chronic manageable disease that is no longer fatal. This review discusses these and other issues relating to prostacyclin and its use in pulmonary arterial hypertension.
Reed DM, Foldes G, Kirkby NS, et al., 2014, Morphology and vasoactive hormone profiles from endothelial cells derived from stem cells of different sources, Biochemical and Biophysical Research Communications, Vol: 455, Pages: 172-177, ISSN: 1090-2104
George PM, Oliver E, Dorfmuller P, et al., 2014, Evidence for the Involvement of Type I Interferon in Pulmonary Arterial Hypertension, CIRCULATION RESEARCH, Vol: 114, Pages: 677-688, ISSN: 0009-7330
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