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Natural-born killers identified by British researchers
September 2009
by Jeffrey Bouley  |  Email the author


LONDON—A team of British researchers, led by Dr. Hugh Brady of Imperial College London's Department of Life Sciences and publishing in the journal Nature Immunology in mid-September, have identified the master gene that causes blood stem cells to turn into disease-fighting natural killer (NK) immune cells. This is a discovery that the team, which included researchers from University College London and the Medical Research Council's National Institute for Medical Research, believes could one day help scientists boost the body's production of these frontline tumor-killing cells, creating new ways to treat cancer.  
NK cells represent a distinct lymphocyte subset that play a "central role in innate immunity," the researchers note, adding that NK cells seem more and more clearly to serve important functions in influencing the nature of the adaptive immune response, such as tumor immunosurveillance and elimination of microbial infection.  
"A great deal of progress has been made in delineating the cytotoxic mechanisms of NK cell action, specifically events that control target cell recognition and receptor signaling, as well as the production of proinflammatory cytokines such as interferon-gamma (IFN-gamma)," the team wrote in their article, "The basic leucine zipper transcription factor NFIL3 is essential for natural killer cell development."
"However, the molecular basis of NK cell development is much less well understood and has been characterized as one of the most important problems to be addressed in NK cell biology," they continued. "Greater knowledge of how NK cells develop into functional effector cells is essential for understanding their contribution to disease processes as well as for exploiting their therapeutic potential."  
The researchers were initially studying the effect of E4bp4 in a very rare but fatal form of childhood leukemia when they discovered its importance for NK cells.  
Currently, NK cells that have been isolated from donated blood will be used at times to treat cancer. However, but the effectiveness of such donated cells is limited because NK cells can be slightly different between one person to another. With this new research in their collective pockets, the British researchers hope to move on to finding a pharmaceutical treatment for cancer patients that will react with the protein expressed by their E4bp4 gene they identified. This would, theoretically, cause their bodies to produce a higher number of NK cells than normal, to increase the chances of successfully destroying tumor, Brady indicates.
"If increased numbers of the patient's own blood stem cells could be coerced into differentiating into NK cells, via drug treatment, we would be able to bolster the body's cancer-fighting force, without having to deal with the problems of donor incompatibility," he says.
In looking at potential immunotherapy applications, the team wrote that that researchers and pharma developers could benefit both from the ability to expand specific subpopulations of NK cells ex vivo or to enhance NK cell numbers in vivo—both of which would be "extremely powerful tools."
Over the course of their work, the team knocked out the E4bp4 gene in a mouse model, creating what they say was the world's first animal model entirely lacking NK cells yet possessing all other blood cells and immune cells. They believe this breakthrough model will not only benefit cancer therapy but also help solve some mysteries around the role of NK cells in autoimmune diseases, such as diabetes and multiple sclerosis.
Some scientists think that these diseases are caused by malfunctioning NK cells that turn on the body and attack healthy cells, causing disease instead of fighting it. Brady notes. Clarifying NK cells' role could lead to new ways of treating these conditions.   This new mouse model should also allow medical researchers, for the first time, to discover if NK cell malfunction is behind even more medical conditions than those already notes, such as inflammatory conditions, persistent viral infections, female infertility and graft rejection.  
"Since shortly after they were discovered in the 1970s, some scientists have suspected that the vital disease-fighting NK cells could themselves be behind a number of serious medical conditions, when they malfunction," Brady notes. "Now finally, with our discovery of the NK cell master gene and subsequent creation of our mouse model, we will be able to find out if the progression of these diseases is impeded or aided by the removal of NK cells from the equation. This will solve the often-debated question of whether NK cells are always the 'good guys' or if, in certain circumstances, they cause more harm than good."  
The study was funded by the non-profit organizations CHILDREN with LEUKAEMIA and Leukaemia Research.
Code: E09230902



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