Immunoproteasome inhibition as a novel therapy for hemophagocytic lymphohistiocytosis (HLH)
Dr. Kim Nichols
St. Jude Children’s Research Hospital
Date of Award:
Amount of Award:
$51,000 (Founder’s Grant and Toughill Prize)
Hemophagocytic lymphohistiocytosis (HLH) is a rare and severe group of diseases affecting the immune system in which patients experience excessive build-up of activated white blood cells within various organs. If HLH is not promptly recognized and treated, these activated white blood cells can damage the organs and lead to death. Current treatments for HLH are aimed at quieting down the overactive immune system with immunosuppressive drugs such as the strong steroid dexamethasone and the chemotherapy medication etoposide. Although these drugs are beneficial, they are associated with significant side effects and less-than-perfect results. For example, about 40% of HLH patients die due to uncontrolled disease or the side effects of its treatment. To win the battle against HLH, we need to come up with better therapies.
Using an animal model of HLH, we plan to test whether a new class of drugs known as “immunoproteasome inhibitors” will help in the treatment of HLH. The immunoproteasome is a protein complex that plays a critical role in the immune system because it degrades intracellular proteins into small molecules known as “peptides” that are presented on the surface of a type of immune cell known as an antigen presenting cell (APC). These peptide-loaded APC are recognized by another type of immune cell known as a CD8+ T cell, which then becomes activated. In HLH, this cycle of T cell activation cannot be shut off naturally, which leads to severe inflammation.
Based on our compelling preliminary data, we propose that immunoproteasome inhibition will reduce immune activation and lessen the features of HLH. In this proposal, we will further examine whether immunoproteasome inhibitors can be safely administered to mice with HLH and evaluate whether and how they impact disease manifestations. If successful, this project will provide us with a new tool with which to combat HLH and improve the outcomes for affected patients.