Tocilizumab Induces IL-10-Mediated Immune Tolerance in Invasive Candidiasis
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)...
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Published in | Journal of fungi (Basel) Vol. 7; no. 8; p. 656 |
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Language | English |
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Abstract | 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-α and IFN-γ responses were not affected. Tocilizumab facilitated immune tolerance by selectively inducing IL-10, producing CD8α+ 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. |
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AbstractList | 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-α and IFN-γ responses were not affected. Tocilizumab facilitated immune tolerance by selectively inducing IL-10, producing CD8α+ 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. 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-α and IFN-γ responses were not affected. Tocilizumab facilitated immune tolerance by selectively inducing IL-10, producing CD8α+ 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. |
Author | Mar Soe, Win Mok, Michelle Meng Huang Tan, Zhaohong Chai, Louis Yi Ann Goh, Jessamine Geraldine Ravikumar, Sharada Thamboo, Thomas Paulraj Sam, Qi Hui Osato, Motomi |
AuthorAffiliation | 1 Department of Medicine, Division of Infectious Diseases, National University Health System, Singapore 119228, Singapore; aiden.tan@hotmail.com (Z.T.); winmarsoe18@gmail.com (W.M.S.); jessamine_goh@sris.a-star.edu.sg (J.G.G.); qihui.sam@nus.edu.sg (Q.H.S.); sharada_ravikumar@nuhs.edu.sg (S.R.) 5 Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore 3 Department of Pathology, National University of Singapore, Singapore 117596, Singapore; pattpt@nus.edu.sg 4 National University Cancer Institute, National University Health System, Singapore 119074, Singapore 2 Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore; micmok@nus.edu.sg (M.M.H.M.); csimo@nus.edu.sg (M.O.) |
AuthorAffiliation_xml | – name: 1 Department of Medicine, Division of Infectious Diseases, National University Health System, Singapore 119228, Singapore; aiden.tan@hotmail.com (Z.T.); winmarsoe18@gmail.com (W.M.S.); jessamine_goh@sris.a-star.edu.sg (J.G.G.); qihui.sam@nus.edu.sg (Q.H.S.); sharada_ravikumar@nuhs.edu.sg (S.R.) – name: 5 Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore – name: 2 Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore; micmok@nus.edu.sg (M.M.H.M.); csimo@nus.edu.sg (M.O.) – name: 4 National University Cancer Institute, National University Health System, Singapore 119074, Singapore – name: 3 Department of Pathology, National University of Singapore, Singapore 117596, Singapore; pattpt@nus.edu.sg |
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SubjectTerms | Candida albicans Candidiasis CD11b antigen Complications Cytokines Dendritic cells Experiments Flow cytometry Fungal infections Immunological tolerance Immunomodulation Immunoregulation Immunosuppressive agents Inflammation Interleukin 10 Interleukin 6 interleukin 6 blockade Kidneys Laboratory animals Ligands Lymphocytes T Monoclonal antibodies monoclonal antibody Morbidity Mortality Transplants & implants Tumor necrosis factor-TNF Tumor necrosis factor-α γ-Interferon |
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Title | Tocilizumab Induces IL-10-Mediated Immune Tolerance in Invasive Candidiasis |
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