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CD16 inhibition increases host survival in a murine model of severe sepsis
Dewen Zhang1, Jian He1, Meihua Shen1
1Department of Emergency and Critical Care Medicine, Changhai Hospital, Shanghai, China.
Background:
To investigate the therapeutic effect of monoclonal antibody (mAb)-induced CD16 (FcγRIII) inhibition in a murine model of high-grade (severe) sepsis.
Materials And Methods:
In a prospective controlled animal study, 2 μg of CD16/32 (FcγRIII/FcγRII) or the same volume of normal saline was administered intraperitoneally to BALB/c FcγRII(-/-) mice at the time of cecal ligation and puncture (CLP) in a murine model of high-grade sepsis. Subcutaneous administration of CD16/32 (0.5 μg/24 h) or normal saline continued for 7 d. Survival was evaluated, and the underlying therapeutic mechanism of mAb-induced CD16 inhibition was investigated.
Results:
CD16 expression was significantly increased on peripheral blood CD14(+) monocytes from mice with high-grade sepsis compared with non-septic control mice (1579.40 ± 217.75 versus 461.10 ± 36.13; P < 0.05). CD16/32 mAb treatment increased the survival of mice with high-grade sepsis (P < 0.05) and significantly decreased their elevated levels of serum tumor necrosis factor α (36.70 ± 9.97 versus 52.60 ± 10.69; P < 0.05) and interleukin 1β (1149.40 ± 244.09 versus 2605.60 ± 353.74; P < 0.05) at 6 and 24 h after CLP, respectively. Moreover, CD16/32 mAb-treated mice with high-grade sepsis had fewer bacteria in their blood and peritoneal lavage than mice just treated with normal saline at 24 h after CLP (P < 0.05).
Conclusions:
CD16/32 mAb-induced CD16 inhibition increased the survival of mice with high-grade sepsis, which may have been because of the concomitant suppression of tumor necrosis factor α and interleukin 1β as well as the enhancement of monocyte phagocytosis. Thus, targeted inhibition of CD16 can potentially improve the outcome of selected patients with severe sepsis.
Insights
Monoclonal antibody (mAb)-induced CD16 inhibition improved survival in a severe sepsis mouse model by reducing inflammatory cytokines and bacterial load. This suggests targeted CD16 inhibition could benefit sepsis patients.
Area of Science:
- Immunology
- Sepsis Pathophysiology
- Therapeutic Antibody Development
Background:
- Severe sepsis is characterized by a dysregulated immune response.
- Monoclonal antibody (mAb)-mediated inhibition of CD16 (FcγRIII) is a potential therapeutic strategy.
- Investigating CD16 inhibition in a murine model of high-grade sepsis.
Purpose of the Study:
- To evaluate the therapeutic efficacy of CD16 inhibition in severe sepsis.
- To elucidate the mechanisms underlying CD16 inhibition's effects.
Main Methods:
- A prospective, controlled animal study using a cecal ligation and puncture (CLP) sepsis model in BALB/c FcγRII(-/-) mice.
- Administration of CD16/32 mAb or saline.
- Monitoring survival, cytokine levels (TNF-α, IL-1β), and bacterial counts.
Main Results:
- CD16 expression was elevated on monocytes in septic mice.
- CD16/32 mAb treatment significantly increased survival rates.
- mAb treatment reduced serum levels of TNF-α and IL-1β.
- Bacterial load in blood and peritoneal lavage was decreased in mAb-treated mice.
Conclusions:
- CD16/32 mAb-induced CD16 inhibition enhances survival in severe sepsis.
- Therapeutic effects are linked to suppressed pro-inflammatory cytokines and improved monocyte phagocytosis.
- Targeted CD16 inhibition shows promise for improving outcomes in severe sepsis patients.
