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Effect of surgical stress on murine natural killer cell cytotoxicity
Abstract:
Natural killer cell cytotoxicity (NKCC) against tumors may be important in preventing in vivo solid tumor dissemination. Multiple animal models demonstrate increased rates of tumor dissemination after surgical stress; previously, we have observed that surgical stress impairs murine NKCC. Because of the importance of surgery in the control of solid tumors, it appeared valuable to examine the mechanism underlying surgical stress impairment of NKCC. The results of this study demonstrate that postsurgical suppression of NKCC begins as early as 2 hr after murine hind limb amputation, reaches nadir at 4 days, and does not recover to control level until postoperative day 12. Anesthetic treatment alone does not cause comparable NKCC suppression. The suppression of NKCC accompanied changes in both splenic size and morphology. The immune suppression was observed in multiple compartments including peripheral blood, bone marrow, and spleen. Mixing experiments demonstrated that surgical stress per se generated a suppressor cell population affecting NKCC. The observed suppression apparently required cell-to-cell contact, because supernatants from 4 and 18 hr cultures of suppressor cells did not cause suppression. The observed suppression was prevented by perioperative treatment with the pyrimidinone analog 2-amino-5-bromo-6-phenyl-4-pyrimidinol. These preclinical observations point to the future prospect of NK-specific perioperative immunotherapy that may help prevent possible tumor dissemination from occurring at the time of surgery.
Insights
Surgical stress significantly impairs natural killer cell cytotoxicity (NKCC) in mice for up to 12 days. This suppression, mediated by suppressor cells, can be prevented by a specific pyrimidinone analog, suggesting perioperative immunotherapy potential.
Area of Science:
- Immunology
- Surgical Oncology
Background:
- Natural killer cell cytotoxicity (NKCC) is crucial for controlling tumor spread.
- Surgical stress is known to increase tumor dissemination rates.
- Previous studies indicate surgical stress impairs NKCC in murine models.
Purpose of the Study:
- To investigate the mechanism by which surgical stress suppresses NKCC.
- To determine the timeline and extent of NKCC suppression post-surgery.
- To identify potential therapeutic interventions to counteract this suppression.
Main Methods:
- Murine hind limb amputation model to induce surgical stress.
- Assessment of NKCC at various time points post-surgery (2 hr to 12 days).
- Analysis of immune cell compartments (spleen, blood, bone marrow) and splenic morphology.
- Co-culture experiments with suppressor cells and NK cells.
- Evaluation of a pyrimidinone analog for preventative effects.
Main Results:
- Postsurgical NKCC suppression begins within 2 hours, peaks at 4 days, and recovers by day 12.
- Anesthesia alone did not induce comparable NKCC suppression.
- Suppression was observed across multiple immune compartments and linked to splenic changes.
- Suppressor cells generated by surgical stress, requiring cell-to-cell contact, were identified.
- Perioperative administration of 2-amino-5-bromo-6-phenyl-4-pyrimidinol prevented NKCC suppression.
Conclusions:
- Surgical stress induces a profound and prolonged suppression of NKCC in mice.
- A cell-contact-dependent suppressor cell population mediates this immune suppression.
- Perioperative immunotherapy targeting NK cells may prevent tumor dissemination during surgery.