Recent Publication: Chemotherapeutic Drug Etoposide Treats Immunoregulatory Disorder

Citation

Johnson TS, Terrell CE, Millen SH, Katz JD, Hildeman DA, Jordan MB. Etoposide Selectively Ablates Activated T Cells To Control the Immunoregulatory Disorder Hemophagocytic Lymphohistiocytosis. J Immunol. 2013 Nov 20. [Epub ahead of print]

 

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is an inborn disorder of immune regulation caused by mutations affecting perforin-dependent cytotoxicity. Defects in this pathway impair negative feedback between cytotoxic lymphocytes and APCs, leading to prolonged and pathologic activation of T cells. Etoposide, a widely used chemotherapeutic drug that inhibits topoisomerase II, is the mainstay of treatment for HLH, although its therapeutic mechanism remains unknown. We used a murine model of HLH, involving lymphocytic choriomeningitis virus infection of perforin-deficient mice, to study the activity and mechanism of etoposide for treating HLH and found that it substantially alleviated all symptoms of murine HLH and allowed prolonged survival. This therapeutic effect was relatively unique among chemotherapeutic agents tested, suggesting distinctive effects on the immune response. We found that the therapeutic mechanism of etoposide in this model system involved potent deletion of activated T cells and efficient suppression of inflammatory cytokine production. This effect was remarkably selective; etoposide did not exert a direct anti-inflammatory effect on macrophages or dendritic cells, and it did not cause deletion of quiescent naive or memory T cells. Finally, etoposide’s immunomodulatory effects were similar in wild-type and perforin-deficient animals. Thus, etoposide treats HLH by selectively eliminating pathologic, activated T cells and may have usefulness as a novel immune modulator in a broad array of immunopathologic disorders.

Visit PubMed Entry

Written by
Allison Brown
View all articles
Written by Allison Brown

About Jagwire

Jagwire is the official source for news and stories from Augusta University and AU Health. Daily updates highlight the many ways students, faculty, staff, researchers and clinicians "bring their A games" in classrooms and clinics on four campuses in Augusta and locations across the state of Georgia. Read on for stories of innovation in education and health care, opportunities at the center of Georgia’s new cybersecurity hub, and experiential learning that blends arts and application, humanities and the health sciences. Have a story to share with Jaguar Nation? Contact the Division of Communications & Marketing.