{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:16:06Z","timestamp":1760235366725,"version":"build-2065373602"},"reference-count":28,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,8,13]],"date-time":"2021-08-13T00:00:00Z","timestamp":1628812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001349","name":"National Medical Research Council","doi-asserted-by":"publisher","award":["NR16NMR137, NR15NMR007, NR18NMR103"],"award-info":[{"award-number":["NR16NMR137, NR15NMR007, NR18NMR103"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JoF"],"abstract":"<jats:p>The existence of a hyperinflammatory state has been observed in patients with invasive fungal infections (IFI). It is being postulated whether morbidity from IFI may, in part, be a consequence of an unnecessarily prolonged or exaggerated proinflammatory immune response including interleukin 6 (IL-6) post-infection, in a host with dysregulated or compromised immunity. This, in turn, induces collateral host injury at the tissue and organ level, leading to adverse outcomes. Tocilizumab has become widely used as an immunomodulator in the treatment of inflammatory conditions. Here, we evaluated the use of tocilizumab to curb post-infective inflammatory flare in the setting of an in-vivo mouse model for invasive candidiasis. Following Candida infection, the tocilizumab-treated mice showed improved short-term survival compared with the saline-treated control mice. There was a reduced inflammatory response mounted by the host, coupled with reduced IL-6 but increased IL-10 levels. TNF-\u03b1 and IFN-\u03b3 responses were not affected. Tocilizumab facilitated immune tolerance by selectively inducing IL-10, producing CD8\u03b1+ conventional dendritic cells (DCs) and peripheral T-regulatory cells, over CD11b+ conventional DCs and plasmacytoid DCs. We demonstrate here the sequelae from immunomodulatory manipulation and the basis whereby the use of monoclonal antibodies may be further explored in IFI.<\/jats:p>","DOI":"10.3390\/jof7080656","type":"journal-article","created":{"date-parts":[[2021,8,13]],"date-time":"2021-08-13T09:22:38Z","timestamp":1628846558000},"page":"656","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Tocilizumab Induces IL-10-Mediated Immune Tolerance in Invasive Candidiasis"],"prefix":"10.3390","volume":"7","author":[{"given":"Zhaohong","family":"Tan","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, National University Health System, Singapore 119228, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle Meng Huang","family":"Mok","sequence":"additional","affiliation":[{"name":"Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Win","family":"Mar Soe","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, National University Health System, Singapore 119228, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas Paulraj","family":"Thamboo","sequence":"additional","affiliation":[{"name":"Department of Pathology, National University of Singapore, Singapore 117596, Singapore"},{"name":"National University Cancer Institute, National University Health System, Singapore 119074, Singapore"},{"name":"Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessamine Geraldine","family":"Goh","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, National University Health System, Singapore 119228, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8450-8519","authenticated-orcid":false,"given":"Qi Hui","family":"Sam","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, National University Health System, Singapore 119228, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3982-9054","authenticated-orcid":false,"given":"Motomi","family":"Osato","sequence":"additional","affiliation":[{"name":"Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore"},{"name":"Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sharada","family":"Ravikumar","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, National University Health System, Singapore 119228, Singapore"},{"name":"National University Cancer Institute, National University Health System, Singapore 119074, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9640-0791","authenticated-orcid":false,"given":"Louis Yi Ann","family":"Chai","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, National University Health System, Singapore 119228, Singapore"},{"name":"National University Cancer Institute, National University Health System, Singapore 119074, Singapore"},{"name":"Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1128\/CMR.00029-06","article-title":"Epidemiology of invasive candidiasis: A persistent public health problem","volume":"20","author":"Pfaller","year":"2007","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1086\/595846","article-title":"Epidemiology and outcome of invasive fungal infection in adult hematopoietic stem cell transplant recipients: Analysis of Multicenter Prospective Antifungal Therapy (PATH) Alliance registry","volume":"48","author":"Neofytos","year":"2009","journal-title":"Clin. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"73","DOI":"10.2217\/fmb.10.158","article-title":"Immune response to Aspergillus fumigatus in compromised hosts: From bedside to bench","volume":"6","author":"Chai","year":"2011","journal-title":"Future Microbiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S189","DOI":"10.1093\/mmy\/myy053","article-title":"Learning to control tissue damage while fighting Aspergillus","volume":"57","author":"Wong","year":"2019","journal-title":"Med. Mycol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1086\/656527","article-title":"Early proinflammatory cytokines and C-reactive protein trends as predictors of outcome in invasive Aspergillosis","volume":"202","author":"Chai","year":"2010","journal-title":"J. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1002\/cncr.22738","article-title":"Immune reconstitution inflammatory syndrome in cancer patients with pulmonary aspergillosis recovering from neutropenia: Proof of principle, description, and clinical and research implications","volume":"110","author":"Miceli","year":"2007","journal-title":"Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Delli\u00e8re, S., Guery, R., Candon, S., Rammaert, B., Aguilar, C., Lanternier, F., Chatenoud, L., and Lortholary, O. (2018). Understanding Pathogenesis and Care Challenges of Immune Reconstitution Inflammatory Syndrome in Fungal Infections. J. Fungi, 4.","DOI":"10.3390\/jof4040139"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"19","DOI":"10.2147\/OARRR.S17118","article-title":"Tocilizumab, a humanized anti-interleukin-6 receptor antibody, for treatment of rheumatoid arthritis","volume":"3","author":"Mihara","year":"2011","journal-title":"Open Access Rheumatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/s41584-020-0419-z","article-title":"Translating IL-6 biology into effective treatments","volume":"16","author":"Choy","year":"2020","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1556\/amicr.61.2014.1.6","article-title":"Serum interleukin-6 levels in murine models of Candida albicans infection","volume":"61","author":"Czudar","year":"2014","journal-title":"Acta Microbiol. Immunol. Hung."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"a016295","DOI":"10.1101\/cshperspect.a016295","article-title":"IL-6 in inflammation, immunity, and disease","volume":"6","author":"Tanaka","year":"2014","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1111\/j.1600-065X.2008.00628.x","article-title":"Th17 cells in human disease","volume":"223","author":"Tesmer","year":"2008","journal-title":"Immunol. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"41744","DOI":"10.1038\/srep41744","article-title":"Basophil-derived IL-6 regulates T(H)17 cell differentiation and CD4 T cell immunity","volume":"7","author":"Yuk","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1007\/s40265-017-0829-7","article-title":"Tocilizumab: A Review in Rheumatoid Arthritis","volume":"77","author":"Scott","year":"2017","journal-title":"Drugs"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Lokau, J., Kleinegger, F., Garbers, Y., Waetzig, G.H., Gr\u00f6tzinger, J., Rose-John, S., Haybaeck, J., and Garbers, C. (2020). Tocilizumab does not block interleukin-6 (IL-6) signaling in murine cells. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0232612"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"926","DOI":"10.3389\/fimmu.2017.00926","article-title":"Tocilizumab Contributes to the Inflammatory Status of Mature Dendritic Cells through Interleukin-6 Receptor Subunits Modulation","volume":"8","author":"Meley","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1146\/annurev-immunol-020711-074950","article-title":"The dendritic cell lineage: Ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting","volume":"31","author":"Merad","year":"2013","journal-title":"Annu. Rev. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1126\/science.1136080","article-title":"Differential antigen processing by dendritic cell subsets in vivo","volume":"315","author":"Dudziak","year":"2007","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2223","DOI":"10.4049\/jimmunol.1601629","article-title":"The Importance of Dendritic Cells in Maintaining Immune Tolerance","volume":"198","author":"Audiger","year":"2017","journal-title":"J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"10729","DOI":"10.1073\/pnas.0601956103","article-title":"The dominant role of CD8+ dendritic cells in cross-presentation is not dictated by antigen capture","volume":"103","author":"Schnorrer","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1111\/j.0105-2896.2004.00142.x","article-title":"Cross-presentation, dendritic cell subsets, and the generation of immunity to cellular antigens","volume":"199","author":"Heath","year":"2004","journal-title":"Immunol. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1182\/blood-2009-01-197178","article-title":"Blockade of interleukin-6 signaling augments regulatory T-cell reconstitution and attenuates the severity of graft-versus-host disease","volume":"114","author":"Chen","year":"2009","journal-title":"Blood"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e1203","DOI":"10.1002\/cti2.1203","article-title":"Tocilizumab monotherapy uncovered the role of the CCL22\/17-CCR4(+) Treg axis during remission of crescentic glomerulonephritis","volume":"9","author":"Sakai","year":"2020","journal-title":"Clin. Transl. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1111\/imr.12816","article-title":"The immunology of Plasmodium vivax malaria","volume":"293","author":"Antonelli","year":"2020","journal-title":"Immunol. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"610","DOI":"10.4161\/viru.21823","article-title":"Dendritic cells, regulatory T cells and the pathogenesis of chronic hepatitis C","volume":"3","author":"Losikoff","year":"2012","journal-title":"Virulence"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.4161\/hv.24726","article-title":"Divergent contributions of regulatory T cells to the pathogenesis of chronic hepatitis C","volume":"9","author":"Self","year":"2013","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.cmi.2020.10.036","article-title":"Efficacy and safety of tocilizumab in COVID-19 patients: A living systematic review and meta-analysis","volume":"27","author":"Tleyjeh","year":"2021","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1056\/NEJMoa1509024","article-title":"Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis","volume":"374","author":"Beardsley","year":"2016","journal-title":"N. Engl. J. 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