Grants Awarded

Genetic Defects in Cytolysis in Patients with Macrophage Activation Syndrome Enrolled in a Clinical Trial to Explore Interleukin-1 Blockage Therapy

Principal Investigator
Randy Cron, M.D., Ph.D.
University of Alabama at Birmingham
Birmingham, AL USA

Date of Award

December 2016

Amount of Award

Layperson Summary
Macrophage activation syndrome (MAS) is related to a group of disorders called hemophagocytic lymphohistiocytosis (HLH), characterized by overly active white blood cells, including histiocytes. Although the genetic or familial form of HLH is rare affecting approximately only one in 50,000 live births, the secondary or acquired forms of HLH (sHLH) and MAS are much more common and can occur at any age of life. It may be that as many as 10% of the general population possess a genetic risk factor for MAS/sHLH, as many of these children and adults have single copy defects/mutations in the same genes responsible for fHLH, which results early in life from gene mutations of both chromosome copies. Both fHLH and sHLH/MAS are frequently fatal conditions requiringaggressive chemotherapy and/or immunosuppression, with high risks of infection and death.

Recently, we and others have noted that blocking a specific inflammatory protein, interleukin-1 (IL-1), in the blood is able to safely and effectively treat many patients with sHLH/MAS, including those with genetic risk factors. IL-1 can be blocked with an engineered protein, anakinra, which is a genetic copy of our ownbody’s IL-1 receptor antagonist. This naturally occurring protein is very short lived requiring daily, or more frequent, injections under the skin. This also makes it remarkably safe as it is gone quickly. Anakinra also benefits sHLH/MAS patients quickly with observable clinical and laboratory improvements typically within 48 hours of treatment.

Based on its effectiveness, safety, and quick action, we were awarded a grant to study the benefit of anakinra in 40 children and adults with sHLH/MAS. As part of this study, we propose to sequence the DNA of the patients in the clinical trial to identify mutations in the genes associated with HLH. In the laboratory, we further plan to study the effects of these mutations on how they contribute to HLH and MAS disease processes. A better understanding of the number of individuals with genetic risk factors for HLH and MAS, as well as knowledge of how these mutations contribute to this histiocytic disease, will help identify individuals at risk and tailor appropriate therapy to those who develop HLH and MAS.