Treatment with lymph node cells controls dangerous sepsis in animal models

August 13, 2014
Researchers identify new treatments for sepsis

An immune-regulating cell present in lymph nodes may be able to halt severe cases of sepsis, an out-of-control inflammatory response that can lead to organ failure and death. In the August 13 issue of Science Translational Medicine, a multi-institutional research team reports that treatment with fibroblastic reticular cells (FRCs) significantly improved survival in two mouse models of sepsis, even when delivered after the condition was well established. Even after treatment with antibiotics, sepsis remains a major cause of death.

"Our findings are important because, to our knowledge, no experimental therapeutic has shown such a significant survival benefit after the disease has progressed so far – in our study up to 16 hours after a -inducing injury," says Biju Parekkadan, PhD, of the Center for Engineering in Medicine at Massachusetts General Hospital (MGH), senior author of the Science Translational Medicine report. "The effectiveness of late treatment is essential because septic patients often do not receive treatment until hours or days after the original injury occurred."

Usually set off when bacteria or other infectious agents invade the bloodstream, sepsis involves an over-reaction of the immune system in which signaling molecules called cytokines attract excessive numbers of immune cells to the site of an infection or injury. Those cells secrete more cytokines, which recruit even more immune cells leading to a vicious cycle called a cytokine storm. Instead of stopping the initial infection, immune factors attack the body's tissues and organs, potentially leading to . Worldwide, more than 140,000 people die from sepsis each week.

Potential sepsis treatments targeting the activity of single molecules have not been successful, the authors note, probably because the condition involves complex interactions among many inflammatory pathways. Treatments using cells, however, can target the action of several molecules, influencing multiple disease pathways and potentially responding to changes in a patient's disease state. Since FRCs are known to regulate many aspects of the immune response within lymph nodes, the researchers investigated whether introducing FRCs to the site of a sepsis-inducing infection could modulate the inflammatory response.

The first experiments used two mouse models – one that uses a bacterial toxin associated with some forms of sepsis, the other in which an injury to the large intestine exposes the abdominal cavity to intestinal contents. The researchers showed that infusing FRCs into the abdominal cavity significantly improved survival in both young and aged mice with toxin-induced sepsis. FRC administration also led to greatly increased survival in the intestinal injury model, which produces a more severe form of sepsis, even though both FRC-treated mice and saline-treated control animals also were treated with antibiotics.

Since the FRCs used in those experiments were cultured from the of the animals to which they were administered, the researchers repeated the experiments using FRCs cultured from an unrelated strain of mice. The increased survival of animals receiving FRCs – with 89 percent surviving versus 14 percent of those treated with saline – implied that cells from healthy human donors could be cultured, stored and used without the need to match immune or other factors in the recipients. The test of treatment delivered well after sepsis was established showed that FRCs delivered 16 hours after a sepsis-inducing injury – instead of 4 hours in the other experiments – also produced a significant survival advantage.

Experiments investigating the mechanism behind the treatment indicated that FRC administration prevented both damage to the spleen – which filters pathogens from the blood – and the death of several types of normally present in the organ. Preservation of spleen function probably explains the reduced levels of bacteria in the bloodstream of FRC-treated animals, even though bacterial levels in the , where sepsis was induced and into which FRCs were infused, remained unchanged. Additional evidence suggested that activity of the signaling molecule nitric oxide may be essential to the effects of FRC treatment.

"The development of FRC therapy for testing in human patients is the critical path we plan to follow, and this study is a good first step," says Parekkadan, an assistant professor of Surgery at Harvard Medical School.

Explore further: Research identifies potential new treatment for sepsis

More information: "Lymph node fibroblastic reticular cell transplants show robust therapeutic efficacy in high-mortality murine sepsis," by A.L. Fletcher et al. … scitranslmed.3009377

Related Stories

Research identifies potential new treatment for sepsis

November 14, 2013
Sepsis is the leading cause of in-hospital death and there is no specific treatment for it. Now, research led by Dr. Qingping Feng of Western University (London, Canada) suggests a protein called recombinant human annexin ...

New perspective on sepsis

April 17, 2014
In a review published in the April issue of Immunity, Kevin J. Tracey, MD, president of The Feinstein Institute for Medical Research, says it's time to take a fresh look at the medical community's approach to treating sepsis, ...

Surviving sepsis with LECT2

December 17, 2012
Failure to launch an adequate immune response may be at the root of septic shock, according to a study published in The Journal of Experimental Medicine on December 17th.

Scientists discover immune system component that resists sepsis in mice

July 9, 2014
Molecular microbiologists from the Keck School of Medicine of the University of Southern California (USC) have discovered that mice lacking a specific component of the immune system are completely resistant to sepsis, a potentially ...

Researchers seek to understand the biology of sepsis in neutropenic patients

May 20, 2014
(Medical Xpress)—Sepsis comes with serious consequences. The blood infection, most commonly caused by bacteria, can lead to septic shock, organ failure, loss of limbs, and even death. Patients whose immune systems are already ...

Molecule regulates production of antibacterial agent used by immune cells

June 20, 2014
Researchers have discovered how a protein molecule in immune cells promotes the production of nitric oxide, a potent weapon in the cells' arsenal to defend the body from bacterial attack. The protein may offer a target for ...

Recommended for you

Make way for hemoglobin

August 18, 2017
Every cell in the body, whether skin or muscle or brain, starts out as a generic cell that acquires its unique characteristics after undergoing a process of specialization. Nowhere is this process more dramatic than it is ...

Two-step process leads to cell immortalization and cancer

August 17, 2017
A mutation that helps make cells immortal is critical to the development of a tumor, but new research at the University of California, Berkeley suggests that becoming immortal is a more complicated process than originally ...

New Pathology Atlas maps genes in cancer to accelerate progress in personalized medicine

August 17, 2017
A new Pathology Atlas is launched today with an analysis of all human genes in all major cancers showing the consequence of their corresponding protein levels for overall patient survival. The difference in expression patterns ...

Female mouse embryos actively remove male reproductive systems

August 17, 2017
A protein called COUP-TFII determines whether a mouse embryo develops a male reproductive tract, according to researchers at the National Institutes of Health and their colleagues at Baylor College of Medicine, Houston. The ...

New technique overcomes genetic cause of infertility

August 17, 2017
Scientists have created healthy offspring from genetically infertile male mice, offering a potential new approach to tackling a common genetic cause of human infertility.

Inhibiting a protein found to reduce progression of Alzheimer's and ALS in mice

August 17, 2017
(Medical Xpress)—A team of researchers with Genetech Inc. and universities in Hamburg and San Francisco has found that inhibiting the creation of a protein leads to a reduction in the progression of Alzheimer's disease ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.