Zoledronate rescues immunosuppressed monocytes in sepsis patients

• Published in: Immunology Vol. 159; no. 1; pp. 88 - 95
• Main Authors: Raffray, Loïc, Burton, Ross J., Baker, Sarah E., Morgan, Matt P., Eberl, Matthias
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.01.2020; John Wiley and Sons Inc
• Subjects: Adult; Aged; Aged, 80 and over; Antigen-presenting cells; Antigens; Biomedical materials; Blood; Bone resorption; Case-Control Studies; CD40 antigen; Clinical outcomes; Cytokines; Female; gammadelta T‐cells; Histocompatibility antigen HLA; HLA-DR Antigens - immunology; HLA-DR Antigens - metabolism; Humans; Immunologic Factors - pharmacology; Immunosuppression; Infections; Inflammation; Interferon; Interferon-gamma - immunology; Interferon-gamma - metabolism; Lymphocytes; Lymphocytes T; Male; Middle Aged; Monocytes; Monocytes - drug effects; Monocytes - immunology; Monocytes - metabolism; Original; Osteoporosis; Paralysis; Peripheral blood; Receptors, Antigen, T-Cell, gamma-delta - immunology; Receptors, Antigen, T-Cell, gamma-delta - metabolism; Sepsis; Sepsis - blood; Sepsis - drug therapy; Sepsis - immunology; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Tumor necrosis factor; Tumor Necrosis Factor-alpha - immunology; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; Tumors; zoledronate; Zoledronic acid; Zoledronic Acid - pharmacology; monocytes; immunosuppression; gammadelta T-cells; zoledronate; sepsis
• ISSN: 0019-2805; 1365-2567; 1365-2567
• DOI: 10.1111/imm.13132

Summary 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 interferon (IFN)‐γ and tumour necrosis factor (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 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. Sepsis is characterised by enhanced susceptibility to secondary infections and poor outcomes as a result of a transient hypoimmune state. Reduced expression of HLA‐DR on circulating monocytes has become a hallmark parameter in those patients that is used both as predictor of mortality and as target for clinical interventions. This study demonstrates that the anti‐bone resorption drug zoledronate has potential in rescuing the immunosuppression in severe sepsis by upregulating the expression of HLA‐DR and other activation markers on monocytes, through a mechanism that depends on the activation of blood γδ T‐cells.