Researchers believe that their breakthrough in cell transplantation could pave the way for new therapies to combat sepsis, the cause of 7.3 million deaths worldwide each year.
The study, published today in Science Translational Medicine, identified novel ways of treating sepsis in mice by withdrawing fibroblastic reticular cells (FRCs) from the lymph nodes and administering these cells in high numbers to those affected.
When treated this way four hours after contracting sepsis there was a 70% reduction in mortality. It is hoped that such significant numbers represent an exciting step forward for treating sepsis in humans.
Septic injury is a life-threatening inflammatory response, triggered by an infection. The immune system goes into overdrive and requires immediate treatment before the body goes into septic shock. At this point the blood pressure is lowered to such a point that people experience multiple organ failure – which often proves fatal.
Dr Anne Fletcher, from the University of Birmingham, explained “Sepsis is particularly dangerous because it is so progressive, it snowballs rapidly, and by the time the patient feels ill enough to act it is already critical. The symptoms are often felt earlier but can be confused with other conditions – flu, chest infections or gastroenteritis, for example.”
Globally it accounts for over 140,000 deaths each week; more than lung cancer, and more than breast cancer and colorectal cancers combined.
Antibiotics form the basis of most current treatments, but new methods are required as infections continue to evolve and develop resistance to these therapies.
Dr Fletcher continued, “This is already a huge problem and we are at more risk than ever before. An ageing population, and the rise of conditions such as Type II Diabetes, puts us at increased risk of contracting the infections that can lead to sepsis. We rely more on surgical interventions, and this puts us at further risk. And, all the while, antibiotic resistance is taking away our main weapon in the fight against sepsis.”
A number of targeted molecular therapies have been trialled with limited success. These tend to target a particular mechanism or process of sepsis and, though often successful in combatting a particular symptom,
fail to ultimately prevent critical organ failure.
Dr Fletcher added, “Sepsis is extraordinarily complex. The therapies trialled in the last few decades have targeted one particular pathway, and we know there to be at least 20 inflammation pathways that we need to consider.”
The research identifies FRCs as having the potential to provide this holistic therapy that supports the immune system across numerous pathways and combats the processes of sepsis.
The FRCs used in the mice were derived from lymph node tissue. Lymph nodes play a vital role in the immune system as they activate the white blood cells that fight infection. Within lymph nodes, FRCs control white blood cells. During sepsis, however, white blood cells are in overdrive and cause the inflammation that drives the disease. By removing FRCs from lymph nodes, expanding them ex-vivo, and inserting them back into the body in high volumes after the onset of sepsis, the researchers saw a marked increase in survival rates and a decrease in a range of inflammatory chemicals produced by white blood cells.
Even when treatment was delayed for 16 hours, survival rate was measured at 44% - compared to 0% in the control group that didn’t receive the therapy.
Dr Fletcher explained what this could mean for future therapeutic developments, “We’ve seen a few therapies go to clinic in the last decade with little success, and in comparison at this early stage of development these results do seem extremely promising. There is a long way to go before we start seeing this in everyday use but these results hopefully represent a significant step.”
The authors of the research have called for further exploration into the role that FRCs could play in sepsis, with a view towards starting clinical trials.
Notes for editors:
There are around 100,000 cases of sepsis admitted to UK hospitals each year, and an estimated 37,000 deaths. 1 in 20 deaths in the UK are associated with sepsis.
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Original research: Anne L. Fletcher, Jessica S. Elman, Jillian Astarita, Ryan Murray, Nima Saeidi, Joshua D’Rozario, Konstantin Knoblich, Flavian D. Brown, Frank A. Schildberg, Janice M. Nieves, Tracy S. P. Heng, Richard L. Boyd, Shannon J. Turley, Biju Parekkadan. Lymph node fibroblastic reticular cell transplants show robust therapeutic efficacy in high-mortality murine sepsis. Science Translational Medicine Vol 6 Issue 249 249ra109.
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