22 June 2020

 

US researchers have revealed a potential new treatment combination for the rare immune disorder haemophagocytic lymphohistiocytosis (HLH).

The condition causes severe hyperinflammation, through immune system overactivation and the production of immune signalling chemicals called cytokines. These chemicals can further activate the immune system, resulting a ‘cytokine storm’ which can lead to organ damage and death.

The research was co-led by Dr Kim Nichols from St Jude Children’s Research Hospital in Memphis, Tennessee and Dr Michelle Hermiston from University of California San Francisco, along with colleagues at Baylor College of Medicine in Houston, Texas.

The team set out to look at how cytokines produced during HLH confer resistance to dexamethasone, one of the standard treatments for the disease.

Dr Nichols explains: “For the last 20 years, treatment for haemophagocytic lymphohistiocytosis has remained a combination of the drugs dexamethasone and etoposide. But we know that many patients either do not respond to this regimen or later relapse, so we dug into the biology to come up with a different treatment strategy.

“We wanted to know whether any of the cytokines that are elevated in haemophagocytic lymphohistiocytosis contribute to dexamethasone resistance, and if so, whether blocking the signalling of these cytokines might reverse treatment resistance.”

The researchers used cells from patients and mouse models of the disease. They found that one particular cytokine, interleukin‑2, is elevated in the condition, and is “critically important to driving resistance to dexamethasone”. Interleukin-2 is produced by activated T cells and promotes their survival.

JAK1/2 mediates the effects interleukin-2 and other cytokines involved in HLH. Therefore, the team hypothesised that adding ruxolitinib, a JAK1/2 inhibitor, might reverse the disease’s resistance to dexamethasone.

They found that blocking the effect of interleukin-2 causes the T cells system to be re-sensitised to dexamethasone. They then found in animal models that the combination of dexamethasone and ruxolitinib to be significantly more effective than either drug alone at controlling HLH.

Publishing their results in the journal Blood, the researchers believe that the study provides further evidence to support testing the combination of dexamethasone and ruxolitinib in clinical trials.


Source: Meyer L, Verbist KC, Albeituni S, Scull BP, Bassett R, Stroh AN, Tillman H, Allen CE, Hermiston M, Nichols KE (2020) “JAK/STAT pathway inhibition sensitizes CD8 T cells to dexamethasone-induced apoptosis in hyperinflammation.” Blood, doi: 10.1182/blood.2020006075

 

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