Tocilizumab Induces IL-10-Mediated Immune Tolerance in Invasive Candidiasis.

Zhaohong Tan,Thomas Paulraj Thamboo,Michelle Meng Huang Mok,Motomi Osato,Win Mar Soe,Sharada Ravikumar,Qi Hui Sam,Louis Yi Ann Chai,Jessamine Geraldine Goh

doi:10.3390/jof7080656

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.

Highlights

Morbidity and mortality rates have remained high in invasive fungal infections (IFI), of which Candidemia is the fourth most common cause of hospital-acquired bloodstream infection worldwide [1]
Comparing the fungal burden in the kidneys after infection, there were no statistically significant differences between tocilizumab-treated and control groups, the tocilizumabtreated mice showed a trend towards slightly higher fungal colony counts (Figure 2C)
Tocilizumab treatment significantly reduced interleukin 6 (IL-6) production in mice splenocytes that were stimulated with Candida, as well as with LPS and P3C through TLR4 and TLR2 pathways, respectively (Figure 3A)

Summary

Introduction

Morbidity and mortality rates have remained high in invasive fungal infections (IFI), of which Candidemia is the fourth most common cause of hospital-acquired bloodstream infection worldwide [1]. Despite the current array of anti-fungal armamentarium available for treatment, all-cause mortality related to invasive candidiasis is still in excess of 30% These figures are especially significant given the ever-increasing numbers of immunocompromised patients who are at-risk in the specialties of hematology, oncology, transplantation, and critical care medicine [2]. It is well-recognized that susceptibility to IFI and adverse outcomes are attributable to an impaired host immune response, which is inadequate at mounting an adequate defense upon encountering the fungal pathogen. This raises the question whether the modulation of an inflammatory flare following fungal infection may in turn alter outcomes

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