Etoposide Selectively Ablates Activated T Cells To Control the Immunoregulatory Disorder Hemophagocytic Lymphohistiocytosis
Open accessAbstract
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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Cyclophosphamide and etoposide are often effective in patients with primary HLH, secondary HLH including macrophage activation syndrome, and corresponding models.
“Cyclophosphamide and etoposide, which are broadly cytotoxic but particularly effective at eliminating activated CD8+ T cells, are often effective in patients with primary HLH, secondary HLH (including macrophage activation syndrome), and corresponding models.75”
From Cytokine storm (2020) · cites this paper as [75]
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Dose translation from animal to human studies revisited.
Reagan‐Shaw, S., Nihal, M., & Ahmad, N. (2008) · The FASEB Journal · doi:10.1096/fj.07-9574lsf · Cited by 6,524 · see citing works
HLH‐2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis
Henter, J., Horne, A., Aricò, M., Egeler, R. M., Filipovich, A. H., Imashuku, S., Ladisch, S., McClain, K. L., Webb, D. K. H., Winiarski, J. H., et al. (2006) · Pediatric Blood & Cancer · doi:10.1002/pbc.21039 · Cited by 5,396 · see citing works
How I treat hemophagocytic lymphohistiocytosis
Jordan, M. B., Allen, C. E., Weitzman, S. S., Filipovich, A. H., & McClain, K. L. (2011) · Blood · doi:10.1182/blood-2011-03-278127 · Cited by 1,145 · see citing works
Self-citationEtoposide: four decades of development of a topoisomerase II inhibitor
Hande, K. R. (1998) · European Journal of Cancer · doi:10.1016/s0959-8049(98)00228-7 · Cited by 948 · see citing works
Henter, J. (2002) · Blood · doi:10.1182/blood-2002-01-0172 · Cited by 900 · see citing works
Ahmed, R., Salmi, A. A., Butler, L. D., Chiller, J. M., & Oldstone, M. B. A. (1984) · The Journal of Experimental Medicine · doi:10.1084/jem.160.2.521 · Cited by 792 · see citing works
Jordan, M. B., Hildeman, D., Kappler, J., & Marrack, P. (2004) · Blood · doi:10.1182/blood-2003-10-3413 · Cited by 712 · see citing works
Self-citationTrottestam, H., Horne, A., Aricò, M., Egeler, R. M., Filipovich, A. H., Gadner, H., Imashuku, S., Ladisch, S., Webb, D. K. H., Janka, G., et al. (2011) · Blood · doi:10.1182/blood-2011-06-356261 · Cited by 684 · see citing works
Familial hemophagocytic lymphohistiocytosis
Janka, G. (1983) · European Journal of Pediatrics · doi:10.1007/bf00443367 · Cited by 576 · see citing works
Crawford, F., Kozono, H., White, J., Marrack, P., & Kappler, J. W. (1998) · Immunity · doi:10.1016/s1074-7613(00)80572-5 · Cited by 459 · see citing works
Janka, G. (2007) · Blood Reviews · doi:10.1016/j.blre.2007.05.001 · Cited by 456 · see citing works
High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease
Luznik, L., Bolaños‐Meade, J., ZAHURAK, M. L., Chen, A. R., Smith, B. D., Brodsky, R. A., Huff, C. A., Borrello, I., Matsui, W. H., Powell, J. D., et al. (2010) · Blood · doi:10.1182/blood-2009-11-251595 · Cited by 409 · see citing works
Senter, P. D., Saulnier, M. G., Schreiber, G. J., Hirschberg, D. L., BROWN, J. P., Hellström, I., & Hellström, K. E. (1988) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.85.13.4842 · Cited by 236 · see citing works
Hemophagocytosis causes a consumptive anemia of inflammation
Zoller, E. E., Lykens, J. E., Terrell, C. E., Aliberti, J., Filipovich, A. H., Henson, P. M., & Jordan, M. B. (2011) · Journal of Experimental Medicine · doi:10.1084/jem.20102538 · Cited by 228 · see citing works
Self-citationBu, H., Zuo, X.-L., Wang, X., Ensslin, M. A., Koti, V., Hsueh, W., Raymond, A. S., Shur, B. D., & Tan, X. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31841 · Cited by 210 · see citing works
Perforin is a critical physiologic regulator of T-cell activation
Lykens, J. E., Terrell, C. E., Zoller, E. E., Risma, K., & Jordan, M. B. (2011) · Blood · doi:10.1182/blood-2010-12-324533 · Cited by 150 · see citing works
Self-citationNewton, K., & Strasser, A. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.191.1.195 · Cited by 144 · see citing works
Metabolism and action of purine nucleoside analogs
Plunkett, W. K., & Saunders, P. P. (1991) · Pharmacology & Therapeutics · doi:10.1016/0163-7258(91)90057-s · Cited by 141 · see citing works
Migration and differentiation of CD8+ T cells
Weninger, W., Manjunath, N., & von Andrian, U. H. (2002) · Immunological Reviews · doi:10.1034/j.1600-065x.2002.18618.x · Cited by 141 · see citing works
Terrell, C. E., & Jordan, M. B. (2013) · Blood · doi:10.1182/blood-2013-04-495309 · Cited by 138 · see citing works
Self-citationFischer, A., Virelizier, J. L., Arenzana‐Seisdedos, F., Pérez, N., Nézelof, C., & Griscelli, C. (1985) · PEDIATRICS · doi:10.1542/peds.76.2.263 · Cited by 128 · see citing works
Spontaneous regression in non-Hodgkin's lymphoma
Gattiker, H. H., Wiltshaw, E., & Galton, D. A. G. (1980) · Cancer · doi:10.1002/1097-0142(19800515)45:10 · Cited by 113 · see citing works
Toxicity of the topoisomerase I inhibitors
Seiter, K. P. (2005) · Expert Opinion on Drug Safety · doi:10.1517/14740338.4.1.45 · Cited by 109 · see citing works
Toxicity of the topoisomerase II inhibitors
Seiter, K. P. (2005) · Expert Opinion on Drug Safety · doi:10.1517/14740338.4.2.219 · Cited by 107 · see citing works
Activation of apoptosis pathways in peripheral blood lymphocytes by in vivo chemotherapy
Stahnke, K., Fulda, S., Friesen, C., Strauß, G., & Debatin, K. (2001) · Blood · doi:10.1182/blood.v98.10.3066 · Cited by 103 · see citing works
Wood, L. J., Nail, L. M., Perrin, N., Elsea, C. R., Fischer, A. M., & Druker, B. J. (2006) · Biological Research For Nursing · doi:10.1177/1099800406290932 · Cited by 94 · see citing works
Pajic, M., Iyer, J. K., Kersbergen, A. J., van der Burg, E., Nygren, A. O. H., Jonkers, J., Borst, P., & Rottenberg, S. (2009) · Cancer Research · doi:10.1158/0008-5472.can-09-0041 · Cited by 93 · see citing works
Ferraro‐Peyret, C., Quéméneur, L., Fournel, S., Prigent, A.-F., Révillard, J. P., & Bonnefoy, N. (2000) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4400595 · Cited by 67 · see citing works
Fadeel, B., Orrenius, S., & Henter, J. (1999) · British Journal of Haematology · doi:10.1046/j.1365-2141.1999.01538.x · Cited by 58 · see citing works
Familial haemophagocytic reticulosis.
Bell, R. J., Brafield, A. J., Barnes, N. D., & France, N. E. (1968) · Archives of Disease in Childhood · doi:10.1136/adc.43.231.601 · Cited by 56 · see citing works
Treatment Outcomes with CHOP Chemotherapy in Adult Patients with Hemophagocytic Lymphohistiocytosis
Shin, H., Chung, J. S., Lee, J., Sohn, S. K., Choi, Y. J., Kim, Y., Yang, D., Kim, H., Kim, J. G., Joo, Y. D., et al. (2008) · Journal of Korean Medical Science · doi:10.3346/jkms.2008.23.3.439 · Cited by 48 · see citing works
Dicker, A. P., Waltham, M. C., Volkenandt, M., Schweitzer, B. I., Otter, G. M., Schmid, F. A., Sirotnak, F. M., & Bertino, J. R. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.24.11797 · Cited by 41 · see citing works
Contemporary diagnostic methods for hemophagocytic lymphohistiocytic disorders
Johnson, T. S., Villanueva, J. M., Filipovich, A. H., Marsh, R. A., & Bleesing, J. (2010) · Journal of Immunological Methods · doi:10.1016/j.jim.2010.11.006 · Cited by 39 · see citing works
Self-citationBarbon, C. M., Yang, M., Wands, G. D., Ramesh, R., Slusher, B. S., Hedley, M. L., & Luby, T. M. (2010) · Cellular Immunology · doi:10.1016/j.cellimm.2010.02.007 · Cited by 36 · see citing works
Ben, S., Li, X., Xu, F., Xu, W., Li, W., Wu, Z., Huang, H., Shi, H., & Shen, H. (2008) · Allergy · doi:10.1111/j.1398-9995.2008.01747.x · Cited by 31 · see citing works
Pharmacokinetics of VP16-213 in Lewis lung carcinoma bearing mice
Colombo, T., Broggini, M., Torti, L., Erba, E., & D’Incalci, M. (1982) · Cancer Chemotherapy and Pharmacology · doi:10.1007/bf00254534 · Cited by 28 · see citing works
THE DISTRIBUTION, METABOLISM, AND ELIMINATION OF CLOFARABINE IN RATS
Bonate, P. L., Arthaud, L. E., Stuhler, J., Yerino, P., Press, R. J., & Rose, J. Q. (2005) · Drug Metabolism and Disposition · doi:10.1124/dmd.104.002592 · Cited by 25 · see citing works
Shin, J. N., Seo, Y. W., Kim, M., Park, S., Lee, M., Lee, B. R., Oh, J., Seol, D., & Kim, T. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m413865200 · Cited by 23 · see citing works
Saif, M. W., & von Borstel, R. W. (2005) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-005-0129-x · Cited by 19 · see citing works
Etoposide‐related secondary acute myeloid leukemia (t‐AML) in hemophagocytic lymphohistiocytosis
Imashuku, S. (2006) · Pediatric Blood & Cancer · doi:10.1002/pbc.21082 · Cited by 18 · see citing works
Eliminating Encephalitogenic T Cells without Undermining Protective Immunity
McNally, J. P., Elfers, E. E., Terrell, C. E., Grunblatt, E., Hildeman, D. A., Jordan, M. B., & Katz, J. D. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1301891 · Cited by 17 · see citing works
Self-citationJc, D., Fessler, B. J., Tassiulas, I. O., McInnes, I. B., Yarboro, C. H., Pillemer, S. R., Wilder, R. L., Fleisher, T. A., Jh, K., & Boumpas, D. T. (1998) · PubMed · Cited by 16 · see citing works
Novel approaches to therapy for systemic lupus erythematosus
Zandman‐Goddard, G., & Shoenfeld, Y. (2000) · European Journal of Internal Medicine · doi:10.1016/s0953-6205(00)00074-1 · Cited by 15 · see citing works
Cervi, D., Klement, G. L., Stempak, D., Baruchel, S., Koki, A. T., & Ben‐David, Y. (2005) · Clinical Cancer Research · doi:10.1158/1078-0432.712.11.2 · Cited by 14 · see citing works
Slater, L. M., Stupecky, M., Sweet, P. M., & Osann, K. (2002) · Leukemia Research · doi:10.1016/s0145-2126(01)00105-9 · Cited by 9 · see citing works
Parker, W. B., Shaddix, S. C., Gilbert, K. S., Shepherd, R. V., & Waud, W. R. (2008) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-008-0862-z · Cited by 9 · see citing works
Flagged first, then by citations
2 of the 48 references couldn’t be matched to a known paper.
Cited by
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Fajgenbaum, D. C., & June, C. H. (2020) · New England Journal of Medicine · doi:10.1056/nejmra2026131 · Cited by 3,196 · see citing works
Recommendations for the management of hemophagocytic lymphohistiocytosis in adults
Rosée, P. G. L., Horne, A., Hines, M., Greenwood, T. V. B., Machowicz, R., Berliner, N., Birndt, S., Gil-Herrera, J., Girschikofsky, M., Jordan, M. B., et al. (2019) · Blood · doi:10.1182/blood.2018894618 · Cited by 1,127 · see citing works
Self-citationCOVID-19: Transmission, prevention, and potential therapeutic opportunities
Lotfi, M., Hamblin, M. R., & Rezaei, N. (2020) · Clinica Chimica Acta · doi:10.1016/j.cca.2020.05.044 · Cited by 1,029 · see citing works
Bergsten, E., Horne, A., Aricò, M., Astigarraga, I., Egeler, R. M., Filipovich, A. H., Ishii, E., Janka, G., Ladisch, S., Lehmberg, K., et al. (2017) · Blood · doi:10.1182/blood-2017-06-788349 · Cited by 677 · see citing works
Hemophagocytic syndromes — An update
Janka, G., & Lehmberg, K. (2014) · Blood Reviews · doi:10.1016/j.blre.2014.03.002 · Cited by 461 · see citing works
Santomasso, B., Nastoupil, L. J., Adkins, S., Lacchetti, C., Schneider, B. J., Anadkat, M., Atkins, M. B., Brassil, K. J., Caterino, J. M., Chau, I., et al. (2021) · Journal of Clinical Oncology · doi:10.1200/jco.21.01992 · Cited by 429 · see citing works
How I treat hemophagocytic lymphohistiocytosis in the adult patient
Schram, A. M., & Berliner, N. (2015) · Blood · doi:10.1182/blood-2015-01-551622 · Cited by 415 · see citing works
Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome
Hines, M., Knight, T. E., McNerney, K. O., Leick, M. B., Jain, T., Ahmed, S., Frigault, M. J., Hill, J. A., Jain, M. D., Johnson, W. T., et al. (2023) · Transplantation and Cellular Therapy · doi:10.1016/j.jtct.2023.03.006 · Cited by 357 · see citing works
Review: Cytokine Storm Syndrome: Looking Toward the Precision Medicine Era
Behrens, E. M., & Koretzky, G. A. (2017) · Arthritis & Rheumatology · doi:10.1002/art.40071 · Cited by 304 · see citing works
Maus, M. V., Alexander, S., Bishop, M. R., Brudno, J. N., Callahan, C. A., Davila, M. L., Diamonte, C., Dietrich, J., Fitzgerald, J. C., Frigault, M. J., et al. (2020) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2020-001511 · Cited by 282 · see citing works
Ahmed, A. Z., Merrill, S. A., Alsawah, F., Bockenstedt, P. L., Campagnaro, E. L., Devata, S., Gitlin, S. D., Kaminski, M. S., Cusick, A., Phillips, T. J., et al. (2019) · The Lancet Haematology · doi:10.1016/s2352-3026(19)30156-5 · Cited by 257 · see citing works
Hemophagocytic Lymphohistiocytosis
Henter, J. (2025) · New England Journal of Medicine · doi:10.1056/nejmra2314005 · Cited by 221 · see citing works
Arca, M., Fardet, L., Galicier, L., Rivière, S., Marzac, C., Aumont, C., Lambotte, O., & Coppo, P. (2014) · British Journal of Haematology · doi:10.1111/bjh.13102 · Cited by 209 · see citing works
Brisse, E., Wouters, C. H., & Matthys, P. (2014) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2014.10.001 · Cited by 206 · see citing works
Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis
Chinn, I. K., Eckstein, O. S., Peckham‐Gregory, E. C., Goldberg, B. R., Forbes, L. R., Nicholas, S. K., Mace, E. M., Vogel, T. P., Abhyankar, H. A., Díaz, M. I., et al. (2018) · Blood · doi:10.1182/blood-2017-11-814244 · Cited by 200 · see citing works
Aston, W. J., Hope, D. E., Nowak, A. K., Robinson, B. W. S., Lake, R., & Lesterhuis, W. J. (2017) · BMC Cancer · doi:10.1186/s12885-017-3677-7 · Cited by 190 · see citing works
Lehmberg, K., Nichols, K. E., Henter, J., Girschikofsky, M., Greenwood, T. V. B., Jordan, M. B., Kumar, A. R., Minkov, M., Rosée, P. G. L., & Weitzman, S. S. (2015) · Haematologica · doi:10.3324/haematol.2015.123562 · Cited by 188 · see citing works
Self-citationPathophysiology and epidemiology of hemophagocytic lymphohistiocytosis
Allen, C. E., & McClain, K. L. (2015) · Hematology · doi:10.1182/asheducation-2015.1.177 · Cited by 164 · see citing works
McClain, K. L., Bigenwald, C., Collin, M. P., Haroche, J., Marsh, R. A., Mérad, M., Picarsic, J. L., Ribeiro, K. B., & Allen, C. E. (2021) · Nature Reviews Disease Primers · doi:10.1038/s41572-021-00307-9 · Cited by 159 · see citing works
Lin, M., Park, S., Hayden, A. R., Giustini, D., Trinkaus, M. A., Pudek, M. R., Mattman, A., Schneider, M., & Chen, L. Y. C. (2017) · Annals of Hematology · doi:10.1007/s00277-017-2993-y · Cited by 150 · see citing works
Liu, P., Pan, X., Chen, C., Niu, T., Shuai, X., Wang, J., Chen, X., Liu, J., Guo, Y. C., Xie, L., et al. (2020) · Blood · doi:10.1182/blood.2019003886 · Cited by 142 · see citing works
Pathophysiology of Pediatric Multiple Organ Dysfunction Syndrome
Carcillo, J. A., Podd, B. S., Aneja, R. K., Weiss, S. L., Hall, M. W., Cornell, T. T., Shanley, T. P., Doughty, L., & Nguyen, T. C. (2017) · Pediatric Critical Care Medicine · doi:10.1097/pcc.0000000000001052 · Cited by 113 · see citing works
Wu, Y., Sun, X., Kang, K., Yang, Y., Li, H., Zhao, A., & Niu, T. (2024) · Journal of Hematology & Oncology · doi:10.1186/s13045-024-01621-x · Cited by 113 · see citing works
Brisse, E., Matthys, P., & Wouters, C. H. (2016) · British Journal of Haematology · doi:10.1111/bjh.14144 · Cited by 102 · see citing works
Treatment of hemophagocytic lymphohistiocytosis in adults
Rosée, P. G. L. (2015) · Hematology · doi:10.1182/asheducation-2015.1.190 · Cited by 101 · see citing works
Wang, H., Xiong, L., Tang, W., Zhou, Y., & Li, F. (2017) · Oncotarget · doi:10.18632/oncotarget.19230 · Cited by 98 · see citing works
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Bami, S., Vagrecha, A., Soberman, D., Badawi, M., Cannone, D., Lipton, J. M. M., Cron, R. Q., & Levy, C. F. (2020) · Pediatric Blood & Cancer · doi:10.1002/pbc.28581 · Cited by 92 · see citing works
Li, X., Shao, M., Zeng, X., Qian, P., & Huang, H. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00764-4 · Cited by 92 · see citing works
Kan, F. K., Tan, C. C., Greenwood, T. V. B., Khalid, K. E., Supramaniam, P., Myrberg, I. H., Tan, L., & Henter, J. (2019) · Clinical Infectious Diseases · doi:10.1093/cid/ciz499 · Cited by 72 · see citing works
Targeting Wee1 kinase as a therapeutic approach in Hematological Malignancies
Vakili‐Samiani, S., Jalil, A. T., Abdelbasset, W. K., Yumashev, A. V., Karpisheh, V., Jalali, P., Adibfar, S., Ahmadi, M., Feizi, A. A. H., & Jadidi‐Niaragh, F. (2021) · DNA repair · doi:10.1016/j.dnarep.2021.103203 · Cited by 72 · see citing works
Strategic development of AZD1775, a Wee1 kinase inhibitor, for cancer therapy
Fu, S., Wang, Y., Keyomarsi, K., & Meric-Bernstein, F. (2018) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2018.1511700 · Cited by 71 · see citing works
Lin, H., Scull, B., Goldberg, B. R., Abhyankar, H. A., Eckstein, O. S., Zinn, D. J., Lubega, J., Agrusa, J. E., Mallawaney, N. E., Gulati, N., et al. (2021) · Blood Advances · doi:10.1182/bloodadvances.2021004287 · Cited by 68 · see citing works
Self-citationManipulating DNA damage-response signaling for the treatment of immune-mediated diseases
McNally, J. P., Millen, S. H., Chaturvedi, V., Lakes, N., Terrell, C. E., Elfers, E. E., Carroll, K. R., Hogan, S. P., Andreassen, P. R., Kanter, J., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1703683114 · Cited by 62 · see citing works
Self-citationRiding the storm: managing cytokine-related toxicities in CAR-T cell therapy
Hughes, A. D., Teachey, D. T., & Diorio, C. J. (2024) · Seminars in Immunopathology · doi:10.1007/s00281-024-01013-w · Cited by 61 · see citing works
Ghosh, S., Carmo, M., Calero-Garcia, M., Ricciardelli, I., Bustamante‐Ogando, J. C., Blundell, M. P., Schambach, A., Ashton‐Rickardt, P. G., Booth, C., Ehl, S. R., et al. (2018) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2017.11.050 · Cited by 59 · see citing works
Familial Hemophagocytic Lymphohistiocytosis
Degar, B. A. (2015) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2015.06.008 · Cited by 55 · see citing works
Horne, A., Greenwood, T. V. B., Chiang, S. C. C., Meeths, M., Björklund, C., Ekelund, M., Erensjö, P., Berg, S., Hagelberg, S., Bryceson, Y. T., et al. (2021) · The Journal of Rheumatology · doi:10.3899/jrheum.200941 · Cited by 54 · see citing works
Song, Y., Wang, Y., & Wang, Z. (2019) · British Journal of Haematology · doi:10.1111/bjh.15988 · Cited by 50 · see citing works
Palmblad, K., Schierbeck, H., Sundberg, E., Horne, A., Harris, H. E., Henter, J., Antoine, D. J., & Andersson, U. (2014) · Molecular Medicine · doi:10.2119/molmed.2014.00183 · Cited by 50 · see citing works
RetractedCoagulation Disorders in Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome
Valade, S., Mariotte, É., & Azoulay, É. (2020) · Critical Care Clinics · doi:10.1016/j.ccc.2019.12.004 · Cited by 49 · see citing works
Major, A., Collins, J., Craney, C., Heitman, A. K., Bauer, E., Zerante, E., Stock, W., Bishop, M. R., & Jasielec, J. K. (2021) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428194.2021.1881507 · Cited by 48 · see citing works
Mechanisms and management of CAR T toxicity
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Haemophagocytic lymphohisticytosis—an underrecognized hyperinflammatory syndrome
Hutchinson, M., Tattersall, R. S., & Manson, J. J. (2019) · Lara D. Veeken · doi:10.1093/rheumatology/kez379 · Cited by 46 · see citing works
Medulloblastoma rendered susceptible to NK-cell attack by TGFβ neutralization
Powell, A. B., Yadavilli, S., Saunders, D., Pelt, S. N. V., Chorvinsky, E. A., Burga, R. A., Albihani, S., Hanley, P. J., Xu, Z., Pei, Y., et al. (2019) · Journal of Translational Medicine · doi:10.1186/s12967-019-2055-4 · Cited by 44 · see citing works
Advances of podophyllotoxin and its derivatives: Patterns and mechanisms
Shi, R.-J., Fan, H., Yu, X., Tang, Y., Jiang, J., & Liang, X. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.115039 · Cited by 43 · see citing works
Nguyen, T. T. T., Kim, Y. T., Jeong, G., & Jin, M. (2024) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01182-6 · Cited by 43 · see citing works
Proliferation through activation: hemophagocytic lymphohistiocytosis in hematologic malignancy
Vick, E. J., Patel, K., Prouet, P., & Martin, M. G. (2017) · Blood Advances · doi:10.1182/bloodadvances.2017005561 · Cited by 42 · see citing works
Abdel‐Bar, H. M., Walters, A. A., Wang, J. T.-W., & Al‐Jamal, K. T. (2021) · Advanced Healthcare Materials · doi:10.1002/adhm.202001853 · Cited by 41 · see citing works
Macrophage Activation Syndrome
Nigrovic, P. A. (2024) · Arthritis & Rheumatology · doi:10.1002/art.43052 · Cited by 40 · see citing works
Diagnosis and Management of Adult Malignancy-Associated Hemophagocytic Lymphohistiocytosis
Lee, J. C., & Logan, A. C. (2023) · Cancers · doi:10.3390/cancers15061839 · Cited by 39 · see citing works
Käsmann, L., Eze, C., Taugner, J., Roengvoraphoj, O., Dantes, M., Schmidt-Hegemann, N.-S., Schiopu, S., Belka, C., & Manapov, F. (2020) · Radiation Oncology · doi:10.1186/s13014-020-01595-3 · Cited by 39 · see citing works
Treatment of hemophagocytic lymphohistiocytosis
Wang, Y., & Wang, Z. (2016) · Current Opinion in Hematology · doi:10.1097/moh.0000000000000302 · Cited by 38 · see citing works
Wegehaupt, O., Wustrau, K., Lehmberg, K., & Ehl, S. R. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00808 · Cited by 36 · see citing works
Song, Y., Wang, Z., Hao, Z., Li, L., Lu, J., Kang, H., Lu, Y. E., You, Y., Li, L., Chen, Q., et al. (2019) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-019-1033-5 · Cited by 35 · see citing works
Ruxolitinib-based regimen in children with primary hemophagocytic lymphohistiocytosis
Ge, J., Zhang, Q., Ma, H., Wang, D., Zhao, Y., Zhu, T., Wang, W., Zhou, C., Wei, A., Lian, H., et al. (2023) · Haematologica · doi:10.3324/haematol.2023.283478 · Cited by 34 · see citing works
Dying to protect: cell death and the control of T‐cell homeostasis
Li, K., Shanmuganad, S., Carroll, K. R., Katz, J. D., Jordan, M. B., & Hildeman, D. A. (2017) · Immunological Reviews · doi:10.1111/imr.12538 · Cited by 34 · see citing works
Self-citationFugere, T., Baltz, A., Mukherjee, A., Gaddam, M., Varma, A., Veeraputhiran, M. K., & Sanchez, C. G. (2023) · Cancers · doi:10.3390/cancers15215149 · Cited by 33 · see citing works
Schutt, S. D., Wu, Y., Kharel, A., Bastian, D. A., Choi, H.-J., Sofi, M. H., Mealer, C., Mims, B. M., Nguyen, H. D., Liu, C., et al. (2022) · Journal of Clinical Investigation · doi:10.1172/jci143950 · Cited by 32 · see citing works
Etoposide as Salvage Therapy for Cytokine Storm Due to Coronavirus Disease 2019
Patel, M., Dominguez, E., Sacher, D. C., Desai, P., Chandar, A., Bromberg, M. E., Caricchio, R., & Criner, G. J. (2020) · CHEST Journal · doi:10.1016/j.chest.2020.09.077 · Cited by 28 · see citing works
Etoposide-based therapy for severe forms of COVID-19
Hamizi, K., Aouidane, S., & Belaaloui, G. (2020) · Medical Hypotheses · doi:10.1016/j.mehy.2020.109826 · Cited by 27 · see citing works
Song, Y., Wang, J., Wang, Y., Wu, L., & Wang, Z. (2021) · Cancer Biology & Therapy · doi:10.1080/15384047.2021.1996139 · Cited by 27 · see citing works
Hemophagocytic lymphohistiocytosis: an update for nephrologists
Filippone, E. J., & Farber, J. L. (2016) · International Urology and Nephrology · doi:10.1007/s11255-016-1294-z · Cited by 27 · see citing works
Yang, Z. R., Xie, Y., Song, J., Liu, R., Chen, J., Weitz, D. A., Sheng, J., Liang, T., & Chen, D. (2024) · Advanced Functional Materials · doi:10.1002/adfm.202407112 · Cited by 28 · see citing works
Wimmer, T., Mattes, R., Stemmler, H., Hauck, F. H., Schulze‐Koops, H., Stecher, S.-S., Starck, M., Wendtner, C., Bojko, P., Hentrich, M., et al. (2022) · Blood Advances · doi:10.1182/bloodadvances.2022007953 · Cited by 26 · see citing works
Miranda‐Vera, C., Hernández, Á., Garcı́a, P. G., David Diez, A., García, P. A., & Castro, M. A. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15122728 · Cited by 27 · see citing works
Diagnosis, Treatment, and Management of Hemophagocytic Lymphohistiocytosis in the Critical Care Unit
Hines, M., Bhatt, N. S., & Talano, J. (2019) · Springer eBooks · doi:10.1007/978-3-030-01322-6_9 · Cited by 25 · see citing works
Combined IFN-γ and JAK inhibition to treat hemophagocytic lymphohistiocytosis in mice
Joly, J.-A., Vallée, A., Bourdin, B., Bourbonnais, S., Patey, N., Gaboury, L. A., Théorêt, Y., & Decaluwe, H. (2022) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2022.07.026 · Cited by 25 · see citing works
Keenan, C., Albeituni, S., Oak, N., Stroh, A. N., Tillman, H. S., Wang, Y., Freeman, B. B., Alemán-Arteaga, S., Meyer, L. K., Woods, R., et al. (2024) · Blood · doi:10.1182/blood.2023021046 · Cited by 24 · see citing works
Immune Effector Cell-associated Hemophagocytic Lymphohistiocytosis-like Syndrome (IEC-HS)
Lee, J. C., Johnson, W. T., Hines, M., & Shah, N. N. (2025) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2025.02.005 · Cited by 26 · see citing works
Chaturvedi, V., Lakes, N., Tran, M., Castillo, N., & Jordan, M. B. (2021) · Blood · doi:10.1182/blood.2020007930 · Cited by 24 · see citing works
Self-citationSecondary hemophagocytic lymphohistiocytosis in children (Review)
Benevenuta, C., Mussinatto, I., Orsi, C., & Timeus, F. S. (2023) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2023.12122 · Cited by 25 · see citing works
Pan, H., Huo, Y., & Sun, L. (2019) · BMC Pediatrics · doi:10.1186/s12887-019-1702-5 · Cited by 24 · see citing works
Dengue-Induced Hemophagocytic Lymphohistiocytosis: A Case Report and Literature Review
Munshi, A., Alsuraihi, A. K., Balubaid, M. M., Althobaiti, M., & Althaqafi, A. O. (2021) · Cureus · doi:10.7759/cureus.20172 · Cited by 23 · see citing works
Safety of CAR-T Cell Therapy in Patients With Renal Failure/Acute Kidney Injury: Focused Review
Khan, I., Khan, N., Wolfson, N., Djebabria, K., Rehman, M. E. U., & Anwer, F. (2023) · Clinical Hematology International · doi:10.1007/s44228-023-00037-7 · Cited by 24 · see citing works
Wang, R., Li, T., Ye, S., Lv, L., Chen, S., Wang, X., Bao, C.-D., & Fu, Q. (2022) · Clinical Rheumatology · doi:10.1007/s10067-022-06184-1 · Cited by 22 · see citing works
Ohmura, S., Uehara, K., Yamabe, T., Tamechika, S., Maeda, S., & Naniwa, T. (2020) · Modern Rheumatology Case Reports · doi:10.1080/24725625.2020.1741073 · Cited by 21 · see citing works
Possible role of low-dose etoposide therapy for hemophagocytic lymphohistiocytosis by COVID-19
Takami, A. (2020) · International Journal of Hematology · doi:10.1007/s12185-020-02888-9 · Cited by 21 · see citing works
Pan, H., Wang, G., Guan, E., Song, L., Song, A., Liu, X., Yi, Z., & Sun, L. (2020) · BMC Pediatrics · doi:10.1186/s12887-020-02178-7 · Cited by 21 · see citing works
Meng, G., Wang, Y., Wang, J., & Wang, Z. (2020) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428194.2020.1849671 · Cited by 21 · see citing works
Lee, B. J., Cao, Y. T. K. H., Vittayawacharin, P., É'Leima, G., Rezk, S. A., Reid, J., Brem, E. A., Ciurea, S. O., & Kongtim, P. (2023) · European Journal Of Haematology · doi:10.1111/ejh.14030 · Cited by 20 · see citing works
Karki, R., Netea, M. G., Diorio, C., & Kanneganti, T. (2026) · Nature Reviews Disease Primers · doi:10.1038/s41572-025-00677-4 · Cited by 20 · see citing works
Miosge, L. A., Sontani, Y., Chuah, A., Horikawa, K., Russell, T., Mei, Y., Wagle, M. V., Howard, D. R., Enders, A., Tscharke, D. C., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1705795114 · Cited by 18 · see citing works
Eliminating Encephalitogenic T Cells without Undermining Protective Immunity
McNally, J. P., Elfers, E. E., Terrell, C. E., Grunblatt, E., Hildeman, D. A., Jordan, M. B., & Katz, J. D. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1301891 · Cited by 17 · see citing works
Self-citationSong, G., Jung, S., Ahn, S., Jung, S.-Y., Yang, D., Ahn, J., Kim, H., & Lee, J. (2019) · BMC Cancer · doi:10.1186/s12885-019-5285-1 · Cited by 17 · see citing works
Du, L., Zhang, L., Li, L., Li, X., Yan, J., Wang, X., Fu, X., Sun, Z., Zhang, X., Li, Z., et al. (2020) · OncoTargets and Therapy · doi:10.2147/ott.s262039 · Cited by 17 · see citing works
Wei, L., Yang, L., Cong, J., Ye, J., Li, X., Yao, N., Yang, H. J., Ding, J., & Wang, J. (2020) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-020-03376-7 · Cited by 17 · see citing works
Trovik, L. H., Sandnes, M., Blomberg, B., Holmaas, G., Ahmed, A. B., Tvedt, T. H. A., Vintermyr, O. K., & Reikvam, H. (2020) · Journal of Medical Case Reports · doi:10.1186/s13256-020-02555-x · Cited by 17 · see citing works
Zeng, X., Wei, N., Wang, Y., Wang, J., Zhang, J., Wu, L., Huang, W., Gao, Z., Pei, R., Chen, J., et al. (2015) · PubMed Central · doi:10.3760/cma.j.issn.0253-2727.2015.06.013 · Cited by 17 · see citing works
Complementary HLH susceptibility factors converge on CD8 T-cell hyperactivation
Landy, E., Varghese, J., Dang, V., Szymczak-Workman, A. L., Kane, L., & Canna, S. (2023) · Blood Advances · doi:10.1182/bloodadvances.2023010502 · Cited by 16 · see citing works
Palmblad, K., Schierbeck, H., Sundberg, E., Horne, A., Harris, H. E., Henter, J., & Andersson, J. (2021) · Molecular Medicine · doi:10.1186/s10020-021-00308-0 · Cited by 16 · see citing works
The Liver in Hemophagocytic Lymphohistiocytosis
Diamond, T., Bennett, A. D., & Behrens, E. M. (2023) · Journal of Pediatric Gastroenterology and Nutrition · doi:10.1097/mpg.0000000000003807 · Cited by 15 · see citing works
Hyperferritinemic Sepsis: An Opportunity for Earlier Diagnosis and Intervention?
Halstead, E. S., Rajasekaran, S., Fitzgerald, J. C., & Weiss, S. L. (2016) · Frontiers in Pediatrics · doi:10.3389/fped.2016.00077 · Cited by 15 · see citing works
From febrile pancytopenia to hemophagocytic lymphohistiocytosis-associated organ dysfunction
Carcillo, J. A., Podd, B. S., & Simon, D. W. (2017) · Intensive Care Medicine · doi:10.1007/s00134-017-4853-6 · Cited by 15 · see citing works
Yang, J., & Yan, B. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1009546 · Cited by 14 · see citing works
Pan, D., & Richter, J. R. (2023) · Cancer Management and Research · doi:10.2147/cmar.s372237 · Cited by 13 · see citing works
History of Hemophagocytic Lymphohistiocytosis
Janka, G. (2024) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-59815-9_2 · Cited by 12 · see citing works
Management of Hemophagocytic Lympho-Histiocytosis in Critically Ill Patients
Lemiale, V., Valade, S., Calvet, L., & Mariotte, É. (2018) · Journal of Intensive Care Medicine · doi:10.1177/0885066618810403 · Cited by 12 · see citing works
Zhang, L.-N., Guo, W., Zhu, J., & Guo, Y. (2018) · World Journal of Clinical Cases · doi:10.12998/wjcc.v6.i13.659 · Cited by 12 · see citing works
Narrative review of chronic active EBV infection—advances in clinical management
Sawada, A., & Inoue, M. (2021) · Annals of Lymphoma · doi:10.21037/aol-20-34 · Cited by 12 · see citing works
McKeone, D. J., DeMartini, T. K. M., Kavanagh, R. P., & Halstead, E. S. (2021) · Frontiers in Pediatrics · doi:10.3389/fped.2021.681055 · Cited by 12 · see citing works
- Authors
- Johnson, T. S., Terrell, C. E., Millen, S. H., Katz, J. D., Hildeman, D. A., & Jordan, M. B.
- Affiliations
- Augusta University (US)
- Cincinnati Children's Hospital Medical Center (US)
- Corresponding author
- Jordan, Michael B
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-01-01
- Volume
- 192
- Issue
- 1
- Pages
- 84-91
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC4177106
- OpenAlex
- W2105957247
- Cited by
- 203
- References
- 48
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 29 · 2023: 19 · 2022: 17 · 2021: 20 · 2020: 28 · 2019: 18 · 2018: 12 · 2017: 19 · 2016: 8 · 2015: 8 · 2014: 4 · 2013: 1
- FWCI
- 5.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL091769)
- National Institute of Allergy and Infectious Diseases (U54AI082973)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK081175)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30AR047363)
- Topics
- Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- hemophagocytic lymphohistiocytosis, etoposide, perforin deficiency, topoisomerase II inhibition, cytotoxic T lymphocytes, lymphocytic choriomeningitis virus, inflammatory cytokines, immunomodulation, innate immune regulation
- MeSH terms
- Animals, Dendritic Cells, Disease Models, Animal, DNA-Binding Proteins, Etoposide, Interferon-gamma, Lymphocyte Activation, Lymphocytic choriomeningitis virus, Macrophage Activation, Macrophages, T-Lymphocytes, Apoptosis, Antigen Presentation, Mice, Knockout, Lymphohistiocytosis, Hemophagocytic, Mice, Topoisomerase II Inhibitors
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