title: Atiprimod (SK&F 106615), a novel macrophage targeting agent, enhances alveolar macrophage candidacidal activity and is not immunosuppressive in Candida-infected mice.
abstract: 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.
authors.affiliation: Department of Bone and Cartilage Biology, Smith Kline Beecham Pharmaceuticals Research and Development, King of Prussia, PA 19406-0939, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Badger
authors.forename: J A
authors.initials: JA
authors.lastname: Handler
authors.forename: C A
authors.initials: CA
authors.lastname: Genell
authors.forename: D
authors.initials: D
authors.lastname: Herzyk
authors.forename: E
authors.initials: E
authors.lastname: Gore
authors.forename: R
authors.initials: R
authors.lastname: Polsky
authors.forename: L
authors.initials: L
authors.lastname: Webb
authors.forename: P J
authors.initials: PJ
authors.lastname: Bugelski
mesh_terms: D000165:Acridine Orange; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology*; D002177:Candidiasis / Q000188:drug therapy / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005260:Female; D005456:Fluorescent Dyes; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008247:Lysosomes; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000276:immunology* / Q000382:microbiology; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D051381:Rats; D011917:Rats, Inbred Lew; D013141:Spiro Compounds / Q000494:pharmacology*
chemical_list: D000276:Adjuvants, Immunologic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000935:Antifungal Agents; D005456:Fluorescent Dyes; D007166:Immunosuppressive Agents; D013141:Spiro Compounds; C099015:azaspirane; D000165:Acridine Orange