Certain interleukins — proteins that can boost inflammation — promote resistance to the corticosteroid dexamethasone (DEX), a first-line treatment for hemophagocytic lymphohistiocytosis (HLH), a study shows. These proteins activate a signaling pathway called JAK/STAT.
Combining DEX with the JAK/STAT inhibitor ruxolitinib helped control inflammation more effectively, the researchers found.
The study, “JAK/STAT pathway inhibition sensitizes CD8 T cells to dexamethasone-induced apoptosis in hyperinflammation,” was published in the journal Blood.
T-cells infiltrate tissues, especially the liver and spleen, and secrete pro-inflammatory signaling molecules, or cytokines, including interleukins. These originate what is called a cytokine storm syndrome — a fatal whole-body (systemic) hyper-inflammation.
A particular subtype of T-cells, known as CD8 T-cells, is a key player in cytokine storm syndrome.
DEX, a glucocorticoid that works as an anti-inflammatory agent, is used in combination with the chemotherapeutic agent etoposide to promote a programmed cell death — a process called apoptosis — of T-cells in HLH patients.
However, more than 30% of HLH cases show resistance to this treatment, resulting in a worse prognosis. Moreover, estimates show that almost 40% of children with HLH have complications resulting from uncontrolled inflammation, despite treatment.
In previous studies, researchers at the St. Jude Children’s Research Hospital and others have shown that interleukins induce resistance to DEX in young patients with T-cell acute lymphoblastic leukemia (T-ALL). These molecules were observed to activated a pathway — called the JAK/STAT pathway — that protected T-cells from DEX-induced cell death.
Now, scientists at the University of California, San Francisco (UCSF), in collaboration with colleagues at St. Jude, investigated whether interleukins also could be responsible for DEX resistance in HLH.
First, the team screened the blood of patients with active HLH for cytokines. Compared with controls, they saw that cytokines — including IFN-gamma, its effector CXCL9, TNF-alpha, and interleukin-6 (IL-6) — were elevated in a subset of patients.
In addition, a component of the interleukin-2 (IL-2) receptor called CD25 was found to be increased. An IL-2 receptor is a marker of T-cell activation and is associated with their survival.
These molecules were tested to determine if they could induce DEX resistance in healthy CD8 T-cells isolated from mice.
The researchers found that IL-2 and another cytokine, called IL-12, promoted the T-cells’ resistance to DEX but not to the chemotherapeutic agent etoposide. None of the other factors tested had an effect on treatment resistance.
At the molecular level, the team found that IL-2 and IL-12 boosted the JAK/STAT pathway, which caused T-cells to become insensitive to DEX.
“Like in leukemia [a disease also treated with DEX], we were able to show that a specific cytokine signaling through the JAK pathway could promote resistance to treatment,” Michelle Hermiston, MD, PhD, from the UCSF department of pediatrics (hematology/oncology), and a co-senior author of the study, said in a UCSF news story.
To learn more, the scientists used a mouse model of HLH disease called PRF1 knock-out, which was engineered to lack the gene PRF1. Mutations in that gene are the cause of familial HLH type 2. Comparing that model with control healthy mice, the researchers showed that IL-2 was able to promote DEX-resistance in CD8 T-cells in living animals, in line with the results seen in isolated cells.
Given these results, the researchers investigated whether targeting the JAK/STAT signaling pathway could be used as a therapy in HLH. They treated the HLH mouse model with DEX and ruxolitinib (RUX), a JAK1/2 inhibitor approved to treat certain rare blood cancers. It is sold as Jakafi in the U.S. and Jakavi elsewhere.
Although RUX has been previously shown to be a potent agent in this model of HLH, the combination of RUX and DEX provided an even greater positive effect on disease symptoms, especially inflammation, than either treatment alone.
St. Jude now plans to test this new protocol, according to UCSF.
“We are hopeful that by adding JAK inhibition to their therapy, we can improve outcomes for patients,” Hermiston said.
Moreover, this discovery may “have important implications for other inflammatory diseases,” Hermiston added, including children with T-ALL leukemia.
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