Bisphosphonates are potent inhibitors of bone resorption in vivo and are emerging as important and widely used drugs for the treatment of a variety of abnormal bone resorptive processes. In the current study we investigated the in vitro effects of 4-amino-l-hydroxybutyylidene-l,l-bisphosphonat(aelendronate), a recently developed, ex- tremely potent bisphosphonate, on the immune functions of human peripheral blood mononuclear cells (PBMCs). PBMC proliferation induced by lectins, alloantigens, and a nominal antigen (tetanus toxoid) was inhibited in a dose-dependent manner by alendronate. Pretreatment of monocytes, but not T cells, with the compound at concentrations ranging from to M was inhibitory, indicating that alendronate acts selectively on antigen-presenting cells (APCs).Alendronate did not affect the viability of monocytes or T cells or the expression of cell surface molecules known to play critical roles in antigen presentation. Alendronate exhibited dose- dependent inhibition of the production of interleukin-1P (IL-lP), interleukin-6 (IL-6), and tumor necrosis factor-a (TNF-a) by activated monocytes. The inhibitory effect of M alendronate on PBMC proliferation was reversed by 10 U/ml recombinant rIL-ap, whereas other cytokines such as IL-6, TNF-a,and granulocyte-macrophage colony-stimulating factor (GM-CSF) had no effect. Thus, alendronate acts on monocytes to inhibit their antigen- presentinglaccessory cell functions through a mechanism that can be overcome by exogenous IL-1. The inhibitory effect of this agent on cytokine production may contribute to its inhibitory effect on bone resorption.
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