The effect of zoledronic acid on the function and differentiation of myeloid cells.
OBJECTIVE
Bisphosphonates are widely used for treatment of osteoporosis and metastases of the skeletal system. Recent data suggest that bisphosphonates may not only reduce bone loss but also exert direct anti-tumor, anti-angiogenic and E inverted exclamation markE not T-cell activating effects, properties which depend at least partially on their affinity to phagocytosing and antigen-presenting cells (i.e. osteoclasts and monocytes). The latter represent the major source of dendritic cells (DC). Thus, we determined the immunomodulatory properties of zoledronic acid (ZA), a member of the latest generation of bisphosphonates.


METHODS
Primary human monocytes, macrophages, immature and mature dendritic cells were incubated with increasing doses of ZA for subsequent analysis of cell surface marker expression and cytokine production. In addition, phagocytic and allo-stimulatory properties, differentiation capacity, and NF-kB activation were determined.


RESULTS
Therapeutic doses of ZA inhibited the in vitro generation of DC from monocytes, as shown by an impaired up-regulation of maturation markers. In parallel, ZA also impaired lipopolysaccharide-induced activation of NF-kB, which represents a critical factor for DC differentiation. Accordingly, the activation of allogeneic T cells by ZA-treated DC in a mixed-lymphocyte reaction was significantly reduced. Finally, ZA inhibited the production of tumor necrosis factor-a in monocyte-derived cells and impaired the phagocytic capacity of macrophages and immature DC.


CONCLUSIONS
Therapeutic doses of ZA modulate monocyte, macrophage and DC function and might thereby modulate immune function.
Wolf
Anna Maria
AM
Laboratory of Tumorimmunology, Department of Hematology and Oncology, Innsbruck Medical University, Anichstr. 35, 6020 Innsbruck, Austria. maria.wolf@uibk.ac.at
Rumpold
Holger
H
Tilg
Herbert
H
Gastl
Guenther
G
Gunsilius
Eberhard
E
Wolf
Dominik
D
D015703:Antigens, CD / Q000032:analysis; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology; D004164:Diphosphonates / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007155:Immunologic Factors / Q000494:pharmacology*; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000187:drug effects; D008264:Macrophages / Q000166:cytology; D009000:Monocytes / Q000166:cytology; D022423:Myeloid Cells / Q000166:cytology* / Q000187:drug effects* / Q000502:physiology; D010587:Phagocytosis / Q000187:drug effects; D000077211:Zoledronic Acid
D015703:Antigens, CD; D004164:Diphosphonates; D007093:Imidazoles; D007155:Immunologic Factors; D000077211:Zoledronic Acid