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Prolonged but reversible neutrophil dysfunctions differentially sensitive to granulocyte colony-stimulating factor in
M Lejeune1, A Ferster, B Cantinieaux
1Laboratory of Haematology, Hôpital Universitaire Saint-Pierre, Belgium.
Insights
Childhood acute lymphoblastic leukemia (ALL) chemotherapy impacts polymorphonuclear leucocyte (PMN) function. Intensive treatment reduces oxidative burst, while maintenance therapy increases PMN apoptosis, indicating persistent immune defects.
Area of Science:
- Immunology
- Pediatric Oncology
- Hematology
Background:
- Childhood acute lymphoblastic leukemia (ALL) treatment involves intensive and maintenance chemotherapy phases.
- Polymorphonuclear leucocytes (PMNs) are crucial for immune defense.
- Understanding chemotherapy's impact on PMN function is vital for managing treatment toxicity and infection risk in pediatric ALL patients.
Purpose of the Study:
- To evaluate and compare the toxicity of intensive versus maintenance chemotherapy on polymorphonuclear leucocyte (PMN) functions in children with ALL.
- To assess the functional and apoptotic status of PMNs during different phases of ALL treatment.
- To investigate the potential of granulocyte colony stimulating factor (G-CSF) in ameliorating chemotherapy-induced PMN defects.
Main Methods:
- Chemiluminescence assays to measure H2O2 and O2- production.
- Assessment of bactericidal activity against Gram-positive and Gram-negative bacteria.
- Flow cytometry to analyze PMN apoptosis markers (hypodiploidy, phosphatidylserine expression) and Fcgamma receptor IIIB (CD16) expression.
- Evaluation of G-CSF effects on PMN chemiluminescence, bactericidal activity, and apoptosis.
Main Results:
- During intensive chemotherapy, H2O2 and O2- production by PMNs were significantly decreased.
- Maintenance therapy was associated with increased PMN apoptosis, indicated by hypodiploidy and altered membrane markers.
- PMN bactericidal activity remained low throughout treatment, normalizing only after chemotherapy cessation; G-CSF partially improved bactericidal function but did not impact apoptosis.
Conclusions:
- Pediatric ALL chemotherapy induces significant PMN functional defects and accelerated apoptosis.
- These PMN impairments are partially responsive to G-CSF, highlighting potential therapeutic targets.
- The findings underscore the complex immunomodulatory effects of chemotherapy in pediatric ALL, necessitating further research into immune recovery and supportive strategies.
Abstract:
Treatment of average-risk acute lymphoblastic leukaemia (ALL) in children consists of 6 months of intensive chemotherapy followed by 18 months of maintenance therapy. Polymorphonuclear leucocyte (PMN) functions from children with ALL were studied in order to evaluate and compare the toxicity of the initial intensive treatment with the toxicity of the subsequent less intensive maintenance treatment. H2O2 and O2- production, evaluated by chemiluminescence, were significantly decreased during the intensive period but returned to normal values when maintenance therapy began. In contrast, bactericidal activity against Gram-positive and Gram-negative microorganisms remained at low levels throughout the treatment but returned to normal values in patients off chemotherapy. PMN from patients on maintenance therapy exhibited an excess of morphological changes associated with apoptosis. This was confirmed by standard two-colour flow cytometry which revealed an increase in the number of hypodiploid cells, and increased expression of membrane phosphatidylserine together with a drastic reduction in the expression of the Fcgamma receptor IIIB (CD16). These defective PMN were differentially sensitive to the effects of granulocyte colony stimulating factor (G-CSF): G-CSF induced similar increase in chemiluminescence in control and patient PMN; GSF partially corrected the defective bactericidal activity; G-CSF did not affect the accelerated PMN apoptosis. These observations indicate that ALL children undergoing chemotherapy present PMN defective functions which are partially sensitive or even resistant to G-CSF.