OBJECTIVES: Liposomal clodronate (dichloromethylene diphosphonate) has been used to deplete macrophages and block clearance of opsonized cells in mouse models of autoimmune disease. However, liposomal clodronate (LC) has not been previously evaluated in a large-animal spontaneous autoimmune disease model. Therefore, the safety and efficacy of LC treatment was assessed in normal dogs and in dogs with spontaneous autoimmune hemolytic anemia (AIHA). METHODS: LC was administered intravenously first to healthy dogs and then to dogs with spontaneous, severe AIHA to determine if the treatment was safe and could block clearance of opsonized red blood cells (RBCs) in vivo. Studies were also conducted to assess the in vitro effects of LC on dog macrophages and dendritic cells. RESULTS: Intravenous infusion of low doses of LC was well tolerated and blocked clearance of opsonized RBCs in normal dogs in vivo. LC was taken up by splenic macrophages and dendritic cells in vivo, and induced killing of macrophages and dendritic cells in vitro. Seven dogs with severe, spontaneous AIHA were treated with LC in a pilot study. Treatment was well tolerated, 2 of 7 LC-treated dogs with AIHA had a decrease in RBC clearance, and LC-treated dogs had significantly increased survival times compared to historical control dogs matched for disease severity. CONCLUSIONS: These results indicate that LC can be safely administered intravenously to dogs and that even relatively low doses are capable of blocking RBC clearance and improving outcomes in a spontaneous large-animal model of AIHA. Therefore, additional studies of LC for treatment of autoantibody-mediated cytopenias in dogs and humans may be warranted.
OBJECTIVES: Liposomal clodronate (dichloromethylene diphosphonate) has been used to deplete macrophages and block clearance of opsonized cells in mouse models of autoimmune disease. However, liposomal clodronate (LC) has not been previously evaluated in a large-animal spontaneous autoimmune disease model. Therefore, the safety and efficacy of LC treatment was assessed in normal dogs and in dogs with spontaneous autoimmune hemolytic anemia (AIHA). METHODS:LC was administered intravenously first to healthy dogs and then to dogs with spontaneous, severe AIHA to determine if the treatment was safe and could block clearance of opsonized red blood cells (RBCs) in vivo. Studies were also conducted to assess the in vitro effects of LC on dog macrophages and dendritic cells. RESULTS: Intravenous infusion of low doses of LC was well tolerated and blocked clearance of opsonized RBCs in normal dogs in vivo. LC was taken up by splenic macrophages and dendritic cells in vivo, and induced killing of macrophages and dendritic cells in vitro. Seven dogs with severe, spontaneous AIHA were treated with LC in a pilot study. Treatment was well tolerated, 2 of 7 LC-treated dogs with AIHA had a decrease in RBC clearance, and LC-treated dogs had significantly increased survival times compared to historical control dogs matched for disease severity. CONCLUSIONS: These results indicate that LC can be safely administered intravenously to dogs and that even relatively low doses are capable of blocking RBC clearance and improving outcomes in a spontaneous large-animal model of AIHA. Therefore, additional studies of LC for treatment of autoantibody-mediated cytopenias in dogs and humans may be warranted.
Authors: Kriston F Weaver; John V Stokes; Sagen A Gunnoe; Joyce S Follows; Lydia Shafer; Mais G Ammari; Todd M Archer; John M Thomason; Andrew J Mackin; Lesya M Pinchuk Journal: J Vet Med Res Date: 2014-06-09
Authors: Janaiara A Cunha; Leonardo J M Carvalho; Cesare Bianco-Junior; Márcia C R Andrade; Lilian R Pratt-Riccio; Evelyn K P Riccio; Marcelo Pelajo-Machado; Igor J da Silva; Pierre Druilhe; Cláudio Tadeu Daniel-Ribeiro Journal: Front Cell Infect Microbiol Date: 2017-09-21 Impact factor: 5.293