Research homes in on drug to dampen inflammation fueling life-threatening immune disorder
Researchers know small molecules called cytokines fuel the fire that drives the life-threatening immune disorder hemophagocytic lymphohistiocytosis (HLH). St. Jude investigators recently detailed how the drug ruxolitinib functions like a fuel shut-off valve to dampen the immune response.
Treatment was associated with improved survival in mouse models of HLH compared with a targeted HLH cytokine inhibitor.
“Results of this preclinical study support including ruxolitinib in future clinical trials,” said corresponding author Kim Nichols, MD, Oncology.
The research appeared in the journal Blood.
HLH is a family of rare, related and often-fatal immune disorders characterized by a massive accumulation and overactivation of white blood cells, particularly T cells and macrophages. That results in overproduction of pro-inflammatory cytokines, which drive inflammation resulting in a range of symptoms and organ damage.
Most patients with HLH are treated with drugs (dexamethasone and etoposide) to suppress the immune response to ease symptoms and prevent organ damage. For some patients, drug treatment is followed by bone marrow transplantation. But even with treatment about half of affected individuals die.
Ruxolitinib is a commercially available drug that has U.S. Food and Drug Administration approval for treatment of other conditions. The drug inhibits the Janus kinase (JAK) pathway in cells and blocks signaling from a variety of cytokines.
The cytokines include interferon-gamma, which previous research has shown is a powerful driver of HLH-associated inflammation.
“But cytokines operate in a network, and many different cytokines are elevated in individuals with HLH,” Nichols said. “Ruxolitinib inhibits more than just interferon-γ. These findings suggest that patients with HLH may benefit from ruxolitinib.”
For this study, researchers used mouse models of primary and secondary HLH to compare ruxolitinib treatment with treatment using an antibody that targets just interferon-γ. Primary HLH is caused by inherited mutations. Secondary or non-genetic HLH occurs in response to an infection, autoimmune disorder, cancer or another underlying condition that results in a cytokine storm.
Both treatments reduced anemia and levels of interferon-γ. But ruxolitinib was also associated with additional benefits, including a significant reduction of other pro-inflammatory cytokines. Accumulation and activation of T cells and neutrophils were also reduced in the organs of ruxolitinib-treated mice, but not in the interferon-γ treatment group, and the organs showed little to no inflammation.
Neutrophils are white blood cells that are part of the innate immune system. The innate immune system is part of the body's first line of defense against infections and other threats. This study marks the first-time neutrophils have been associated with the HLH disease process.
“Ruxolitinib works by suppressing the innate as well as the adaptive immune system," said first author Sabrin Albeituni, PhD, a postdoctoral fellow in the Nichols’ laboratory. “The drug appears to do so in a way that relies on blocking interferon-γ as well as other cytokines.”
The other St. Jude authors are Katherine Verbist, PhD, Oncology; Heather Tillman, DVM, PhD, Veterinary Pathology Core; and Paige Tedrick and Rachel Bassett, both formerly of St. Jude.
Latin American hospitals implement tool to identify kids whose condition is deterioratingNov 1, 2022
CDK6: A well-known kinase commits a new ‘crime’ connecting outer radial glia to microcephalySep 27, 2022