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.