Etoposide Selectively Ablates Activated T Cells To Control the Immunoregulatory Disorder Hemophagocytic Lymphohistiocytosis

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ID: 116417
2014
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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.
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johnson2014theetoposide Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Theodore S. Johnson;Catherine E. Terrell;Scott H. Millen;Jonathan D. Katz;David A. Hildeman;Michael B. Jordan;Theodore S. Johnson;Catherine E. Terrell;Scott H. Millen;Jonathan D. Katz;David A. Hildeman;Michael B. Jordan;
Journal the journal of immunology
Year 2014
DOI
10.4049/jimmunol.1302282
URL
http://dx.doi.org/10.4049/jimmunol.1302282
Keywords
National Center for Biotechnology Information NCBI NLM MEDLINE Mice animals pubmed abstract nih national institutes of health national library of medicine research support N.I.H. Extramural Disease Models Animal Apoptosis / drug effects Knockout lymphohistiocytosis etoposide / administration & dosage hemophagocytic / drug therapy* dna-binding proteins / genetics interferon-gamma / biosynthesis t-lymphocytes / immunology* macrophages / drug effects dendritic cells / immunology lymphocyte activation / immunology* apoptosis / immunology pmid:24259502 pmc4177106 doi:10.4049/jimmunol.1302282 theodore s johnson catherine e terrell michael b jordan antigen presentation / drug effects antigen presentation / immunology dendritic cells / drug effects etoposide / pharmacology* lymphocyte activation / drug effects* lymphocytic choriomeningitis virus hemophagocytic / genetics hemophagocytic / immunology* macrophage activation / drug effects macrophage activation / immunology macrophages / immunology t-lymphocytes / drug effects* topoisomerase ii inhibitors / administration & dosage topoisomerase ii inhibitors / pharmacology

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