Zoledronate rescues immunosuppressed monocytes in sepsis patients

Raffray, Loïc, Burton, Ross J., Baker, Sarah E. ORCID: https://orcid.org/0000-0002-7474-9757, Morgan, Matt P. and Eberl, Matthias ORCID: https://orcid.org/0000-0002-9390-5348 2020. Zoledronate rescues immunosuppressed monocytes in sepsis patients. Immunology 159 (1) , pp. 88-95. 10.1111/imm.13132

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Abstract

Severe sepsis is often accompanied by a transient immune paralysis, which is associated with enhanced susceptibility to secondary infections and poor clinical outcomes. The functional impairment of antigen‐presenting cells is considered to be a major hallmark of this septic immunosuppression, with reduced HLA‐DR expression on circulating monocytes serving as predictor of mortality. Unconventional lymphocytes like γδ T cells have the potential to restore immune defects in a variety of pathologies including cancer but their use to rescue sepsis‐induced immunosuppression has not been investigated. Our own previous work showed that Vγ9/Vδ2+ γδ T cells are potent activators of monocytes from healthy volunteers in vitro, and in individuals with osteoporosis after first‐time administration of the anti‐bone resorption drug zoledronate in vivo. We show here that zoledronate readily induces upregulation of HLA‐DR, CD40 and CD64 on monocytes from both healthy controls and sepsis patients, which could be abrogated by neutralising the pro‐inflammatory cytokines IFN‐γ and TNF‐α in the cultures. In healthy controls, the upregulation of HLA‐DR on monocytes was proportional to the baseline percentage of Vγ9/Vδ2 T cells in the PBMC 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 to 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Publisher:	Wiley
ISSN:	0019-2805
Funders:	Wellcome Trust
Date of First Compliant Deposit:	15 October 2019
Date of Acceptance:	7 October 2019
Last Modified:	02 May 2023 23:57
URI:	https://orca.cardiff.ac.uk/id/eprint/126040

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