{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T20:59:17Z","timestamp":1789419557237,"version":"build-2803163510"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2014,1,1]],"date-time":"2014-01-01T00:00:00Z","timestamp":1388534400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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\u2019s 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.<\/jats:p>","DOI":"10.4049\/jimmunol.1302282","type":"journal-article","created":{"date-parts":[[2013,11,20]],"date-time":"2013-11-20T21:37:42Z","timestamp":1384983462000},"page":"84-91","source":"Crossref","is-referenced-by-count":177,"title":["Etoposide Selectively Ablates Activated T Cells To Control the Immunoregulatory Disorder Hemophagocytic Lymphohistiocytosis"],"prefix":"10.1093","volume":"192","author":[{"given":"Theodore S","family":"Johnson","sequence":"first","affiliation":[{"name":"Cancer Immunology, Inflammation and Tolerance Program, Division of Pediatric Hematology\/Oncology, Department of Pediatrics, Georgia Regents University Cancer Center, Georgia Regents University , Augusta, GA 30912"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine E","family":"Terrell","sequence":"additional","affiliation":[{"name":"Division of Immunobiology, Department of Pediatrics, Cincinnati Children\u2019s Hospital Medical Center, University of Cincinnati College of Medicine , Cincinnati, OH 45229"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott H","family":"Millen","sequence":"additional","affiliation":[{"name":"Division of Immunobiology, Department of Pediatrics, Cincinnati Children\u2019s Hospital Medical Center, University of Cincinnati College of Medicine , Cincinnati, OH 45229"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan D","family":"Katz","sequence":"additional","affiliation":[{"name":"Division of Immunobiology, Department of Pediatrics, Cincinnati Children\u2019s Hospital Medical Center, University of Cincinnati College of Medicine , Cincinnati, OH 45229"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A","family":"Hildeman","sequence":"additional","affiliation":[{"name":"Division of Immunobiology, Department of Pediatrics, Cincinnati Children\u2019s Hospital Medical Center, University of Cincinnati College of Medicine , Cincinnati, OH 45229"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael B","family":"Jordan","sequence":"additional","affiliation":[{"name":"Division of Immunobiology, Department of Pediatrics, Cincinnati Children\u2019s Hospital Medical Center, University of Cincinnati College of Medicine , Cincinnati, OH 45229"},{"name":"Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children\u2019s Hospital Medical Center, University of Cincinnati College of Medicine , Cincinnati, OH 45229"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,1,1]]},"reference":[{"key":"2025032404054835900_r1","doi-asserted-by":"crossref","first-page":"4041","DOI":"10.1182\/blood-2011-03-278127","article-title":"How I treat hemophagocytic lymphohistiocytosis","volume":"118","author":"Jordan","year":"2011","journal-title":"Blood"},{"key":"2025032404054835900_r2","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1182\/blood-2003-10-3413","article-title":"An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder","volume":"104","author":"Jordan","year":"2004","journal-title":"Blood"},{"key":"2025032404054835900_r3","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1182\/blood-2010-12-324533","article-title":"Perforin is a critical physiologic regulator of T-cell activation","volume":"118","author":"Lykens","year":"2011","journal-title":"Blood"},{"key":"2025032404054835900_r4","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1084\/jem.20102538","article-title":"Hemophagocytosis causes a consumptive anemia of inflammation","volume":"208","author":"Zoller","year":"2011","journal-title":"J. Exp. Med."},{"key":"2025032404054835900_r5","doi-asserted-by":"crossref","first-page":"5184","DOI":"10.1182\/blood-2013-04-495309","article-title":"Perforin deficiency impairs a critical immunoregulatory loop involving murine CD8(+) T cells and dendritic cells","volume":"121","author":"Terrell","year":"2013","journal-title":"Blood"},{"key":"2025032404054835900_r6","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1002\/pbc.21039","article-title":"HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis","volume":"48","author":"Henter","year":"2007","journal-title":"Pediatr. Blood Cancer"},{"key":"2025032404054835900_r7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jim.2010.11.006","article-title":"Contemporary diagnostic methods for hemophagocytic lymphohistiocytic disorders","volume":"364","author":"Johnson","year":"2011","journal-title":"J. Immunol. Methods"},{"key":"2025032404054835900_r8","doi-asserted-by":"crossref","first-page":"2516","DOI":"10.1002\/1097-0142(19800515)45:10<2516::AID-CNCR2820451008>3.0.CO;2-V","article-title":"Successful treatment of lymphohistiocytic reticulosis with phagocytosis with epipodophyllotoxin VP 16-213","volume":"45","author":"Ambruso","year":"1980","journal-title":"Cancer"},{"key":"2025032404054835900_r9","doi-asserted-by":"crossref","first-page":"2367","DOI":"10.1182\/blood-2002-01-0172","article-title":"Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation","volume":"100","author":"Henter","year":"2002","journal-title":"Blood"},{"key":"2025032404054835900_r10","doi-asserted-by":"crossref","first-page":"4577","DOI":"10.1182\/blood-2011-06-356261","article-title":"Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol","volume":"118","author":"Trottestam","year":"2011","journal-title":"Blood"},{"key":"2025032404054835900_r11","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/BF00443367","article-title":"Familial hemophagocytic lymphohistiocytosis","volume":"140","author":"Janka","year":"1983","journal-title":"Eur. J. Pediatr."},{"key":"2025032404054835900_r12","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1046\/j.1365-2141.1999.01538.x","article-title":"Induction of apoptosis and caspase activation in cells obtained from familial haemophagocytic lymphohistiocytosis patients","volume":"106","author":"Fadeel","year":"1999","journal-title":"Br. J. Haematol."},{"key":"2025032404054835900_r13","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1084\/jem.160.2.521","article-title":"Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice. Role in suppression of cytotoxic T lymphocyte response and viral persistence","volume":"160","author":"Ahmed","year":"1984","journal-title":"J. Exp. Med."},{"key":"2025032404054835900_r14","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1177\/1099800406290932","article-title":"The cancer chemotherapy drug etoposide (VP-16) induces proinflammatory cytokine production and sickness behavior-like symptoms in a mouse model of cancer chemotherapy-related symptoms","volume":"8","author":"Wood","year":"2006","journal-title":"Biol. Res. Nurs."},{"key":"2025032404054835900_r15","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.cellimm.2010.02.007","article-title":"Consecutive low doses of cyclophosphamide preferentially target Tregs and potentiate T cell responses induced by DNA PLG microparticle immunization","volume":"262","author":"Barbon","year":"2010","journal-title":"Cell. Immunol."},{"key":"2025032404054835900_r16","doi-asserted-by":"crossref","first-page":"11797","DOI":"10.1073\/pnas.90.24.11797","article-title":"Methotrexate resistance in an in vivo mouse tumor due to a non-active-site dihydrofolate reductase mutation","volume":"90","author":"Dicker","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032404054835900_r17","doi-asserted-by":"crossref","first-page":"10509","DOI":"10.1074\/jbc.M413865200","article-title":"Cisplatin inactivation of caspases inhibits death ligand-induced cell death in vitro and fulminant liver damage in mice","volume":"280","author":"Shin","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2025032404054835900_r18","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1124\/dmd.104.002592","article-title":"The distribution, metabolism, and elimination of clofarabine in rats","volume":"33","author":"Bonate","year":"2005","journal-title":"Drug Metab. Dispos."},{"key":"2025032404054835900_r19","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1007\/s00280-008-0862-z","article-title":"Enhancement of the in vivo antitumor activity of clofarabine by 1-beta-D-[4-thio-arabinofuranosyl]-cytosine","volume":"64","author":"Parker","year":"2009","journal-title":"Cancer Chemother. Pharmacol."},{"key":"2025032404054835900_r20","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1111\/j.1398-9995.2008.01747.x","article-title":"Treatment with anti-CC chemokine receptor 3 monoclonal antibody or dexamethasone inhibits the migration and differentiation of bone marrow CD34 progenitor cells in an allergic mouse model","volume":"63","author":"Ben","year":"2008","journal-title":"Allergy"},{"key":"2025032404054835900_r21","doi-asserted-by":"crossref","first-page":"6396","DOI":"10.1158\/0008-5472.CAN-09-0041","article-title":"Moderate increase in Mdr1a\/1b expression causes in vivo resistance to doxorubicin in a mouse model for hereditary breast cancer","volume":"69","author":"Pajic","year":"2009","journal-title":"Cancer Res."},{"key":"2025032404054835900_r22","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/0163-7258(91)90057-S","article-title":"Metabolism and action of purine nucleoside analogs","volume":"49","author":"Plunkett","year":"1991","journal-title":"Pharmacol. Ther."},{"key":"2025032404054835900_r23","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1007\/s00280-005-0129-x","article-title":"5-Fluorouracil dose escalation enabled with PN401 (triacetyluridine): toxicity reduction and increased antitumor activity in mice","volume":"58","author":"Saif","year":"2006","journal-title":"Cancer Chemother. Pharmacol."},{"key":"2025032404054835900_r24","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1158\/1078-0432.712.11.2","article-title":"Targeting cyclooxygenase-2 reduces overt toxicity toward low-dose vinblastine and extends survival of juvenile mice with Friend disease","volume":"11","author":"Cervi","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"2025032404054835900_r25","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1034\/j.1600-065X.2002.18618.x","article-title":"Migration and differentiation of CD8+ T cells","volume":"186","author":"Weninger","year":"2002","journal-title":"Immunol. Rev."},{"key":"2025032404054835900_r26","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/S1074-7613(00)80572-5","article-title":"Detection of antigen-specific T cells with multivalent soluble class II MHC covalent peptide complexes","volume":"8","author":"Crawford","year":"1998","journal-title":"Immunity"},{"key":"2025032404054835900_r27","first-page":"3673","article-title":"Milk fat globule-EGF factor 8\/lactadherin plays a crucial role in maintenance and repair of murine intestinal epithelium","volume":"117","author":"Bu","year":"2007","journal-title":"J. Clin. Invest."},{"key":"2025032404054835900_r28","doi-asserted-by":"crossref","first-page":"4842","DOI":"10.1073\/pnas.85.13.4842","article-title":"Anti-tumor effects of antibody-alkaline phosphatase conjugates in combination with etoposide phosphate","volume":"85","author":"Senter","year":"1988","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032404054835900_r29","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1096\/fj.07-9574LSF","article-title":"Dose translation from animal to human studies revisited","volume":"22","author":"Reagan-Shaw","year":"2008","journal-title":"FASEB J."},{"key":"2025032404054835900_r30","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.blre.2007.05.001","article-title":"Hemophagocytic syndromes","volume":"21","author":"Janka","year":"2007","journal-title":"Blood Rev."},{"key":"2025032404054835900_r31","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1007\/BF00254534","article-title":"Pharmacokinetics of VP16-213 in Lewis lung carcinoma bearing mice","volume":"7","author":"Colombo","year":"1982","journal-title":"Cancer Chemother. Pharmacol."},{"key":"2025032404054835900_r32","doi-asserted-by":"crossref","first-page":"1514","DOI":"10.1016\/S0959-8049(98)00228-7","article-title":"Etoposide: four decades of development of a topoisomerase II inhibitor","volume":"34","author":"Hande","year":"1998","journal-title":"Eur. J. Cancer"},{"key":"2025032404054835900_r33","first-page":"263","article-title":"Treatment of four patients with erythrophagocytic lymphohistiocytosis by a combination of epipodophyllotoxin, steroids, intrathecal methotrexate, and cranial irradiation","volume":"76","author":"Fischer","year":"1985","journal-title":"Pediatrics"},{"key":"2025032404054835900_r34","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1136\/adc.43.231.601","article-title":"Familial haemophagocytic reticulosis","volume":"43","author":"Bell","year":"1968","journal-title":"Arch. Dis. Child."},{"key":"2025032404054835900_r35","doi-asserted-by":"crossref","first-page":"439","DOI":"10.3346\/jkms.2008.23.3.439","article-title":"Treatment outcomes with CHOP chemotherapy in adult patients with hemophagocytic lymphohistiocytosis","volume":"23","author":"Shin","year":"2008","journal-title":"J. Korean Med. Sci."},{"key":"2025032404054835900_r36","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/S0953-6205(00)00074-1","article-title":"Novel approaches to therapy for systemic lupus erythematosus","volume":"11","author":"Zandman-Goddard","year":"2000","journal-title":"Eur. J. Intern. Med."},{"key":"2025032404054835900_r37","doi-asserted-by":"crossref","first-page":"3224","DOI":"10.1182\/blood-2009-11-251595","article-title":"High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease","volume":"115","author":"Luznik","year":"2010","journal-title":"Blood"},{"key":"2025032404054835900_r38","first-page":"1694","article-title":"High dose versus low dose fludarabine in the treatment of patients with severe refractory rheumatoid arthritis","volume":"25","author":"Davis","year":"1998","journal-title":"J. Rheumatol."},{"key":"2025032404054835900_r39","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/sj.cdd.4400595","article-title":"The topoisomerase inhibitors camptothecin and etoposide induce a CD95-independent apoptosis of activated peripheral lymphocytes","volume":"7","author":"Ferraro","year":"2000","journal-title":"Cell Death Differ."},{"key":"2025032404054835900_r40","doi-asserted-by":"crossref","first-page":"3066","DOI":"10.1182\/blood.V98.10.3066","article-title":"Activation of apoptosis pathways in peripheral blood lymphocytes by in vivo chemotherapy","volume":"98","author":"Stahnke","year":"2001","journal-title":"Blood"},{"key":"2025032404054835900_r41","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1084\/jem.191.1.195","article-title":"Ionizing radiation and chemotherapeutic drugs induce apoptosis in lymphocytes in the absence of Fas or FADD\/MORT1 signaling. Implications for cancer therapy","volume":"191","author":"Newton","year":"2000","journal-title":"J. Exp. Med."},{"key":"2025032404054835900_r42","doi-asserted-by":"crossref","first-page":"73","DOI":"10.4049\/jimmunol.1301891","article-title":"Eliminating encephalitogenic T cells without undermining protective immunity","volume":"192","author":"McNally","year":"2013","journal-title":"J. Immunol."},{"key":"2025032404054835900_r43","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/S0145-2126(01)00105-9","article-title":"Enhancement of leukemia rejection by mice successfully treated for L1210 leukemia due to low dose compared to high dose VP-16","volume":"26","author":"Slater","year":"2002","journal-title":"Leuk. Res."},{"key":"2025032404054835900_r44","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1517\/14740338.4.2.219","article-title":"Toxicity of the topoisomerase II inhibitors","volume":"4","author":"Seiter","year":"2005","journal-title":"Expert Opin. Drug Saf."},{"key":"2025032404054835900_r45","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1002\/pbc.21082","article-title":"Etoposide-related secondary acute myeloid leukemia (t-AML) in hemophagocytic lymphohistiocytosis","volume":"48","author":"Imashuku","year":"2007","journal-title":"Pediatr. Blood Cancer"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/192\/1\/84\/62510952\/1302282.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/192\/1\/84\/62510952\/1302282.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T00:23:29Z","timestamp":1742775809000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/192\/1\/84\/7993464"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,1,1]]},"references-count":45,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2014,1,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1302282","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2014,1]]},"published":{"date-parts":[[2014,1,1]]}}}