For certain genetic disorders, an infection can trigger an overly aggressive immune response that does more harm than good to the patient. New research suggests that targeting a single enzyme could put the brakes on a lethal immune response triggered by Epstein-Barr virus (EBV) in patients with X-linked lymphoproliferative disease (XLP-1).
The findings were reported in the Jan. 13, 2015, issue of Science Translational Medicine ("Inhibition of diacylglycerol kinase alpha restores restimulation-induced cell death and reduces immunopathology in XLP-1"). Scientists at the Uniformed Services University of the Health Sciences (USU) in Bethesda, Md., led by Dr. Andrew Snow, assistant professor of pharmacology and molecular therapeutics, in collaboration with researchers from the University of Piemonte Orientale in Novara, Italy, and St. Jude's Children's Research Hospital in Memphis, Tenn., studied whether an enzyme known as diacylglycerol kinase alpha (DGKα) rendered T lymphocytes (T cells) from XLP-1 patients more resistant to cell death.
XLP-1, also known as Duncan's disease, is an often-fatal immune disorder in boys characterized, in part, by an over-accumulation of white blood cells including T cells – a key cellular component of the immune response against viruses. These patients are extremely vulnerable to EBV, which infects more than 90 percent of the general population and is usually asymptomatic. In adolescence, EBV can cause infectious mononucleosis (IM) which resolves within several weeks. In contrast, more than 65 percent of XLP-1 patients infected with EBV die from fulminant disease (FIM), in which an overabundance of activated T cells inadvertently invade and destroy healthy tissues (liver, bone marrow, etc.). Currently, XLP-1 can only be cured via bone marrow transplantation.
Previous work by Snow showed that T cells from XLP-1 patients do not die properly in response to repeated stimulation because they lack SLAM-associated protein (SAP). This process of “restimulation-induced cell death” (RICD) helps to maintain a balanced immune response by limiting the number of T cells responding to infection, thereby preventing unintended damage to the body's own tissues. Snow's lab at USU studies RICD and factors that control sensitivity to this form of cell death. In their current study, Snow and his collaborators demonstrated that RICD of XLP-1 patient T cells can be restored by blocking DGKα, which is normally regulated by SAP. Through preclinical testing using both human T cells and a mouse disease model, this study establishes DGKα as a viable, specific drug target to treat XLP-1 patients experiencing EBV-induced FIM - a life-threatening scenario for which more effective treatment strategies are sorely needed for acute care. Although DGKα inhibition may represent a targeted treatment for XLP-1, a rare disease, this study suggests that pharmacological manipulation of RICD sensitivity could be an attractive therapeutic strategy for several immune disorders that feature an overabundance of activated T cells.
Funding for Snow’s work was provided by grants from the National Institutes of Health, the UK-based XLP Research Trust, and USU.
Source: Uniformed Services University of the Health Sciences (USU)