A novel monoclonal antibody treatment developed in collaboration with Northwestern Medicine scientists reduced inflammation and immune dysregulation in mouse models of sepsis, underscoring the antibody’s therapeutic potential, according to a recent study published in Nature Communications.
Sepsis is a life-threatening condition that occurs when the immune system overreacts to an infection. If not immediately treated, sepsis can lead to severe organ damage and even death. According to recent data from the Centers for Disease Control and Prevention, an estimated 1.7 million adults in the U.S. develop sepsis every year and roughly 350,000 will die from the disease.
The rapid administration of antibiotics and other supportive care, including IV fluids, can help fight infection, but this approach only scratches the surface, according to Hasan Alam, MD, chair and the Loyal and Edith Davis Professor of Surgery who was a co-author of the study.
“We give IV fluids and we give antibiotics directed towards the bacteria, but the downstream cascades of what’s happening at the cellular level are often not addressed,” said Alam, who is also a professor of Cell and Developmental Biology. “Even if we kill the bacteria, we also know that even dead bacteria and bacterial debris is also pro-inflammatory, so that’s why antibiotics don’t work right away.”
Sepsis causes immune dysregulation driven by specialized white blood cells called neutrophils. Under normal conditions, neutrophils create neutrophil extracellular traps (NETs) which trap and kill bacteria by releasing citrullinated histone H3 (CitH3), a protein located in the nucleus. In the case of sepsis, the excessive production of NETs can lead to immune dysfunction and tissue damage.
In the current study, Alam and his collaborators aimed to target this immune dysfunction by developing a novel anti-CitH3 monoclonal antibody which binds to CitH3 to regulate inflammation.
“CitH3 is a nuclear protein, and a nuclear protein is supposed to stay in the nucleus, but if it’s shed into the environment, it acts as a pro-inflammatory driver. It causes inflammation, breaks more cells, more histone is released and it perpetuates a vicious cycle of ongoing inflammation. This antibody breaks that cycle by binding to CitH3,” Alam said.
After administering this antibody to mice with sepsis, the scientists found using cell-based assays and cellular imaging techniques a reduction in cytokine production and mortality. They also found reduced acute lung injury caused by bacterial infection and improved bacteria phagocytosis — the process by which immune cells destroy bacteria — in the mice’ lungs, spleen and liver.
Additionally, they discovered the antibody helped restore the function of macrophages, specialized white blood cells that stimulate other immune cells to target foreign antigens.
The findings highlight the therapeutic potential of the anti-CitH3 monoclonal antibody as an additional treatment for sepsis.
The study also underscores the diagnostic and prognostic potential of CitH3 in helping determine whether a bacterial infection is causing sepsis, which can help clinicians determine which patients should receive antibiotic treatment, as well as which patients may require more intensive care, Alam said.
“We don’t have any way of diagnosing whether there’s a bacterial infection or not, so what we found out is that levels of CitH3 in the circulation is a very good marker that this is a bacterial infection,” Alam said. “Depending on the level of this protein in the circulation and whether that protein level responds and drops in response to the treatment, you can prognosticate who is going to get sick with multiple organ failure, who will need ICU care and who will survive.”
The next steps for the research, according to Alam, will include testing a human version of this antibody in clinical trials.
This work was supported by Joint-of-Institute grant U068874 and by National Institutes of Health grants R01HL155116, R01HL157215, R01AG07240, R01EY036243 and R35GM136312.
