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Effects of ifosfamide on immunocompetent effector cells
G Multhoff1, C Botzler, A Allenbacher
1Institut für Klinische Hämatologie, Munich, Germany.
Cancer Immunology, Immunotherapy : CII
|May 1, 1996
Summary
Ifosfamide chemotherapy damages cytotoxic T cells by depleting glutathione (GSH), but not natural killer (NK) cells. NK cells resist ifosfamide due to higher GSH levels and cystine uptake, preserving their cytotoxic activity.
Area of Science:
- Immunology
- Pharmacology
- Cell Biology
Background:
- Ifosfamide is a widely used chemotherapeutic agent.
- Immunocompetent effector cells like cytotoxic T lymphocytes and natural killer (NK) cells are crucial for antitumor immunity.
- Understanding the differential effects of chemotherapy on these immune cells is vital for optimizing cancer therapy.
Purpose of the Study:
- To investigate the in vitro effects of ifosfamide's activated form (4-OH-IF) on cytotoxic T cells and NK cells.
- To determine the mechanisms underlying any observed differential sensitivity.
- To explore potential protective strategies against ifosfamide-induced immunotoxicity.
Main Methods:
- In vitro treatment of activated cytotoxic T cells and NK cells with 4-hydroperoxyifosfamide (4-OOH-IF), which generates 4-OH-IF.
- Assessment of cellular lytic activity against target cells.
- Measurement of intracellular glutathione (GSH) levels.
- Evaluation of thiol (e.g., mesna) and cystine uptake by immune cells.
Main Results:
- 4-OH-IF treatment significantly reduced the cytotoxic activity of T cells, correlating with GSH depletion.
- Thiol supplementation (mesna) restored T cell lytic activity and GSH levels.
- NK cell lytic activity remained largely unaffected by 4-OH-IF.
- NK cells exhibited higher baseline GSH levels, increased GSH synthesis rates, and cystine uptake capacity, contributing to their resistance.
- T cells lacked significant cystine uptake capability.
Conclusions:
- Cytotoxic T cells are more susceptible to ifosfamide-induced cytotoxicity than NK cells due to lower GSH levels and impaired GSH replenishment.
- NK cells possess inherent resistance mechanisms against ifosfamide, including higher GSH levels and the ability to uptake cystine.
- These findings highlight the differential immunomodulatory effects of ifosfamide and suggest strategies to mitigate T cell-mediated immunosuppression during chemotherapy.