Session Type: Abstract Submissions (ACR)
The synovial tissue in rheumatoid arthritis (RA) represents a hypoxic environment with up-regulated pro-inflammatory cytokines and cellular infiltrates including neutrophils. Tocilizumab, a humanized IgG1 monoclonal antibody directed against the interleukin (IL) 6 receptor, is a potent biologic treatment for RA but the inhibition of the IL6 pathway may also cause unwanted effects such as a decrease in blood neutrophil counts and occasionally high grade neutropenia.
In order to understand both therapeutic and adverse effects of IL6 receptor inhibition, we analysed the effects of tocilizumab on survival, phagocytotic capacity and energy metabolism of neutrophils under normoxic versus hypoxic conditions.
Human neutrophils were purified, pre-treated with varying doses of tocilizumab and, for comparison, dexamethasone or vehicle and finally stimulated with lipopolysaccharide (LPS) or left unstimulated. Cells were then incubated under normoxic (18% O2) or hypoxic (1% O2) conditions and subsequently analysed.
Both neutrophil survival and energy availability were significantly decreased by tocilizumab in a dose-dependent manner in LPS stimulated cells, but to a greater extent under normoxia as compared to hypoxia. We also found LPS stimulated phagocytotic activity of neutrophils to be significantly higher under hypoxic versus normoxic conditions, but this difference was significantly reduced by tocilizumab.
Tocilizumab is known for both beneficial effects and a higher incidence of neutropenia (>1/100 bis 1/10) when treating RA patients. Our results suggest that both effects can at least in part be explained by a reduction in neutrophil survival and a dose-dependent inhibition of a hypoxia-induced phagocytic activity of infiltrating hypoxic neutrophils, mimicking conditions of the inflamed joint environment.
AbbVie, Pfizer, UCB, Roche,
AbbVie, BMS, Pfizer, Merck, MedImmune, UCB, Roche,
AbbVie, BMS, Pfizer, Merck, UCB, Roche,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/disentangling-the-effects-of-tocilizumab-on-neutrophil-survival-and-function/