INHIBITION OF ANTIGEN-PRESENTING CELL-FUNCTION BY ALENDRONATE IN-VITRO

Bisphosphonates are potent inhibitors of bone resorption in vivo and a re 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-1-hydroxybutylidene-1,1- bisphosphonate (alendronate), a recently developed, extremely potent b isphosphonate, on the immune functions of human peripheral blood monon uclear cells (PBMCs). PBMC proliferation induced by lectins, alloantig ens, and a nominal antigen (tetanus toroid) was inhibited in a dose-de pendent manner by alendronate. Pretreatment of monocytes, but not T ce lls, with the compound at concentrations ranging from 10(-4) to 10(-8) M was inhibitory, indicating that alendronate acts selectively on ant igen-presenting cells (APCs). Alendronate did not affect the viability of monocytes or T cells or the expression of cell surface molecules k nown to play critical roles in antigen presentation. Alendronate exhib ited dose-dependent inhibition of the production of interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (T NF-alpha) by activated monocytes. The inhibitory effect of 10(-6) M al endronate on PBMC proliferation was reversed by 10 U/ml recombinant rI L-1 beta, whereas other cytokines such as IL-6, TNF-alpha, and granulo cyte-macrophage colony-stimulating factor (GM-CSF) had no effect, Thus , alendronate acts on monocytes to inhibit their antigen-presenting/ac cessory cell functions through a mechanism that can be overcome by exo genous IL-1. The inhibitory effect of this agent on cytokine productio n may contribute to its inhibitory effect on bone resorption.