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The functional impairment of antigen\u2010presenting cells is considered to be a major hallmark of this septic immunosuppression, with reduced HLA\u2010DR expression on circulating monocytes serving as predictor of mortality. Unconventional lymphocytes like \u03b3\u03b4 T\u2010cells have the potential to restore immune defects in a variety of pathologies including cancer, but their use to rescue sepsis\u2010induced immunosuppression has not been investigated. Our own previous work showed that V\u03b39\/V\u03b42<jats:sup>+<\/jats:sup> \u03b3\u03b4 T\u2010cells are potent activators of monocytes from healthy volunteers <jats:italic>in vitro<\/jats:italic>, and in individuals with osteoporosis after first\u2010time administration of the anti\u2010bone resorption drug zoledronate <jats:italic>in vivo<\/jats:italic>. We show here that zoledronate readily induces upregulation of HLA\u2010DR, CD40 and CD64 on monocytes from both healthy controls and sepsis patients, which could be abrogated by neutralising the pro\u2010inflammatory cytokines interferon (IFN)\u2010\u03b3 and tumour necrosis factor (TNF)\u2010\u03b1 in the cultures. In healthy controls, the upregulation of HLA\u2010DR on monocytes was proportional to the baseline percentage of V\u03b39\/V\u03b42 T\u2010cells in the peripheral blood mononuclear cell population. Of note, a proportion of sepsis patients studied here did not show a demonstrable response to zoledronate, predominantly patients with microbiologically confirmed bloodstream infections, compared with sepsis patients with more localised infections marked by negative blood cultures. Taken together, our results suggest that zoledronate can, at least in some individuals, rescue immunosuppressed monocytes during acute sepsis and thus may help improve clinical outcomes during severe infection.<\/jats:p>","DOI":"10.1111\/imm.13132","type":"journal-article","created":{"date-parts":[[2019,10,13]],"date-time":"2019-10-13T11:33:40Z","timestamp":1570966420000},"page":"88-95","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Zoledronate rescues immunosuppressed monocytes in sepsis patients"],"prefix":"10.1111","volume":"159","author":[{"given":"Lo\u00efc","family":"Raffray","sequence":"first","affiliation":[{"name":"Division of Infection and Immunity School of Medicine Cardiff University Cardiff UK"},{"name":"Department of Internal Medicine F\u00e9lix Guyon University Hospital of La R\u00e9union Saint Denis France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross J.","family":"Burton","sequence":"additional","affiliation":[{"name":"Division of Infection and Immunity School of Medicine Cardiff University Cardiff UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah E.","family":"Baker","sequence":"additional","affiliation":[{"name":"Division of Infection and Immunity School of Medicine Cardiff University Cardiff UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matt P.","family":"Morgan","sequence":"additional","affiliation":[{"name":"Directorate of Critical Care, Cardiff &amp; Vale University Health Board University Hospital of Wales Cardiff UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9390-5348","authenticated-orcid":false,"given":"Matthias","family":"Eberl","sequence":"additional","affiliation":[{"name":"Division of Infection and Immunity School of Medicine Cardiff University Cardiff UK"},{"name":"Systems Immunity Research Institute Cardiff University Cardiff UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,11,21]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2011.1829"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3552"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2017.165"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2017.162"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1200690"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0b013e3181ab858a"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-010-1962-x"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/cc10457"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13054-016-1505-0"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm0697-678"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/cc10031"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000002044"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000308"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002040"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1401018"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3384"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2017.10.009"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-019-0153-5"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2008.07435.x"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201242492"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2018.02.007"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.1797"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2009.09.001"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1600990"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s002239900353"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2010.10.177"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/imm.12331"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-017-2011-1"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-03-417519"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2015.1047580"}],"container-title":["Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/imm.13132","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/imm.13132","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/imm.13132","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T04:05:48Z","timestamp":1693973148000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/imm.13132"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,21]]},"references-count":30,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,1]]}},"alternative-id":["10.1111\/imm.13132"],"URL":"https:\/\/doi.org\/10.1111\/imm.13132","archive":["Portico"],"relation":{},"ISSN":["0019-2805","1365-2567"],"issn-type":[{"value":"0019-2805","type":"print"},{"value":"1365-2567","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,21]]},"assertion":[{"value":"2019-09-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-10-07","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-11-21","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}