Imagine that every household in a large city turned on every light switch in their houses at the same time, overloading the electrical power plant. The same kind of scenario happens in cytokine storm syndromes, when overactivation of the immune system produces too many inflammatory molecules (hypercytokinemia) that damage healthy organs. Researchers at Children’s Hospital of Philadelphia are studying small signaling proteins in the IL-1 cytokine family that potentially could be targeted as circuit breakers by drugs used to block the overwhelming immune response.
As a rheumatologist, Edward Behrens, MD, chief of the Division of Rheumatology and the Joseph Lee Hollander Chair in Pediatric Rheumatology at CHOP, encounters a cytokine storm syndrome, also known as macrophage activation syndrome (MAS), in some young patients with systemic juvenile idiopathic arthritis, an autoimmune disorder. The signs and symptoms of MAS are similar to those seen in patients with sepsis who have serious infections usually caused by some type of bacteria or virus; however, in MAS, bacteria aren’t inciting the systemic inflammation. The body's immune system mistakenly attacks some of its own healthy cells and tissues. They experience massive inflammation that progresses to multiorgan failure. A strikingly similar disease process occurs in another disorder called hemophagocytic lymphohistiocytosis (HLH), a rare condition in which the body makes too many immune cells. While the context of these cytokine storm syndromes may differ, all are life-threatening.
“The common theme seems to be that the immune system is spitting out too many cytokines,” said Dr. Behrens, who also is an associate professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania. “If we can figure out which cytokines are actually causing the disease, we could try to block them.”
Dr. Behrens received a new grant from the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, to investigate the cellular and molecular mechanisms that contribute to hypercytokinemia and subsequently find new treatment strategies that could potentially reduce these devastating complications. The project’s main focus is to study the cytokine IL-33, which will benefit from novel insights that Dr. Behrens has gained from tangential work with its sister cytokine, IL-18.
Important Preclinical IL-33 Groundwork
Dr. Behrens’ previous research in mice models of HLH suggests that blocking IL-33 helped the mice get better. IL-33 acts as an “alarmin” that signals increases in another cytokine called interferon-gamma that is produced by CD8 T cells. Interferon-gamma is critical for fighting off viral and bacterial infections, yet excessive amounts cause inflammation that can lead to organ failure in HLH. When the researchers blocked IL-33, interferon-gamma levels in the mice went down. The new grant will allow Dr. Behrens and his study team to take a closer look at how IL-33 could promote inflammatory diseases and under what circumstances.
“We think we have this great target,” Dr. Behrens said. “Now we need to understand in the most minute details how we could treat patients with IL-33 blocking antibodies to cure their HLH. It’s in the realm of possibility because a drug that blocks IL-13 already exists for a completely different purpose. This new grant will help us to provide the rationale and important preclinical data to one day open a clinical trial to see if blocking IL-33 is a safe and effective treatment for humans with HLH.”
This concept could be extended to other examples of conditions where CD8 T cells make too many cytokines. For example, the researchers’ preliminary results in mouse models suggest that blocking IL-33 could be beneficial in graft vs. host disease, which can occur after a bone marrow or stem cell transplant. The donated bone marrow/cells attack the recipient’s body because they view it as foreign. Taku Kambayashi, MD, PhD, an associate professor of Pathology and Laboratory Medicine at Penn Medicine, is working with Dr. Behrens to study how IL-33 works in HLH and graft-host disease animal models.
A Hunch Leads to Novel Intervention
Dr. Behrens’ research interests in the IL-1 family of cytokines enabled him to make a serendipitous connection between a seriously ill infant’s symptoms and a gene called NLRC4 that produces IL-18, another cytokine that contributes to inflammatory processes. He described the life-threatening case of infantile-onset MAS and enterocolitis in an article published early online in the Journal of Allergy and Clinical Immunology.
The six-week-old patient was admitted to CHOP’s pediatric intensive care unit on a weekend that Dr. Behrens was on call, and her condition was getting worse. Dr. Behrens suspected that she had MAS, but one of her symptoms — severe diarrhea — isn’t usually a part of that diagnosis.
Then he recalled a paper that a former CHOP rheumatology fellow who he had trained, Scott Canna, MD, had published in Nature Genetics about a family who had a mutation in NLRC4 that caused the gene to be “turned on” all the time, and as a result they developed MAS and diarrhea. A new attending physician in Immunology at CHOP, Neil Romberg, MD, had independently discovered that the exact same gene caused the exact same syndrome in another family. He reported his findings in the same issue. Dr. Behrens and his colleagues wondered that it would be a massive coincidence if the sick baby under their care could be the fifth person in the world to be diagnosed with NLRC4-MAS.
Their hunch was right. Whole exome testing, a technique for sequencing all the expressed genes in a genome, revealed that the baby had the NLRC4 mutation.
“We knew she had the disease, but the problem was no one knew what to do about it,” Dr. Behrens said. “We tried all of our usual things, and for four months she was in the hospital and was not getting better. Everyone was concerned that if we didn’t try something drastic, this case would not have a good outcome.”
One option was to try a way block IL-18, but finding the right drug wasn’t an easy task. Fortunately, Dr. Behrens discovered a company Switzerland that was testing an IL-18 blocking drug in small clinical trials for some other indications. When Dr. Behrens explained that the drug potentially could help a gravely ill six-month-old who had a gene mutation that caused her to produce too much IL-18, the company and the U.S. Food and Drug Administration agreed that it could be used as an emergency investigational new drug.
“After two doses, it seemed she was cured,” Dr. Behrens said. “She sat up and smiled. The inflammation melted away. Today, you would never know she had been so sick.”
In this breakthrough case, blocking IL-18 indeed was like finding a central circuit breaker to turn off the immune system’s overpowering response. Dr. Behrens and his team are hoping that the same concept holds true for IL-33 and HLH.
“Even if the results aren’t as dramatic, we could have another tool that will help,” Dr. Behrens said. “This patient story demonstrates how our work goes from the bedside, to the bench, to the bedside. What you do in the lab is hopefully motivated by what you see in the clinic. And then, what you do in the clinic will be motivated by what you do in the lab. It’s not one directional, and you need to have the infrastructure that allows you to bridge all those gaps. CHOP is one of the few places in the world where you can do that.”