Azaspiranes are novel macrophage-targeting agents with activity in preclinical animal models of
autoimmune disease and
transplantation. The purpose of this work was to determine the effects of
atiprimod (
SK&F 106615), an
azaspirane being developed for the treatment of
rheumatoid arthritis, on rat pulmonary alveolar macrophage (AM) function and immunocompetance in Candida-infected mice. AM from rats treated with 20 mg/kg/day of
atiprimod for 15 days demonstrated enhanced killing of Candida albicans ex vivo. Concentration-dependent increases in candidacidal activity were also observed as early as one hour after exposure in vitro in AM from untreated normal rats. Treatment of AM with
atiprimod in vitro did not increase particulate-stimulated
superoxide production or phagocytosis of Candida but decreased their ability to concentrate
acridine orange, indicating an increase in lysosomal pH. Increased candidacidal activity was inhibited by
superoxide dismutase and
catalase, suggesting a role for
reactive oxygen intermediates (ROI).
Atiprimod also increased
free radical-mediated killing of Candida in the presence of H2O2,
iron and
iodide in a cell-free system. These findings indicated that treatment with
atiprimod increased the candidacidal activity of rat AM in a
free radical-dependent manner. The data also suggested that
atiprimod did not increase ROI production by AM, but rather increased the efficiency of radical-mediated killing. This increase may be caused by cyclization of
atiprimod, facilitating electron transfer and peroxidation of
lipid membranes. In vivo studies in Candida-infected CBA mice showed that
atiprimod (10 mg/kg/day), did not compromise immune function in the infected mice and could be differentiated from prototypical immunosuppressive compounds used for treatment of
autoimmune diseases.