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Prepublished online as a Blood First Edition Paper on August 29, 2002; DOI 10.1182/blood-2001-11-0061.
Submitted November 27, 2001
Accepted August 15, 2002
Liposomal clodronate as a novel agent for treating autoimmune hemolytic anemia in a mouse model
Michael B Jordan*, Nico van Rooijen, Shozo Izui, John Kappler, and Philippa Marrack
Department of Pediatrics, University of Colorado Health Science Center, Denver, CO, USA; Department of Immunology, National Jewish Medical and Research Center, Denver, CO, USA; Howard Hughes Medical Institute, National Jewish Medical and Research Center, Denver, CO, USA
Department of Cell Biology & Immunology, Vrije Universiteit, Amsterdam, The Netherlands
Department of Pathology, University of Geneva, Geneva, Switzerland; Department of Biochemistry and Molecular Genetics, University of Colorado Health Science Center, Denver, CO, USA
Department of Immunology, National Jewish Medical and Research Center, Denver, CO, USA; Howard Hughes Medical Institute, National Jewish Medical and Research Center, Denver, CO, USA; Department of Pharmacology, University of Colorado Health Science Center, Denver, CO, USA
Department of Immunology, National Jewish Medical and Research Center, Denver, CO, USA; Howard Hughes Medical Institute, National Jewish Medical and Research Center, Denver, CO, USA; Department of Medicine, University of Colorado Health Science Center, Denver, CO, USA
* Corresponding author; email: jordanm{at}njc.org.
Autoimmune hemolytic anemia (AIHA) is a disease in which autoantibodies against red blood cells (RBC's) lead to their premature destruction. Most clinically significant autoantibodies are of the IgG type, which lead primarily to the uptake and destruction of RBC's by splenic and hepatic macrophages. Therapies such as corticosteroids and splenectomy are directed at interfering with this process. Liposomally encapsulated clodronate (dichloromethylene diphosphonate) has previously been found to be a potent anti-macrophage agent. It selectively depletes animals of macrophages within 24 hours of administration by inducing apoptosis in these cells. Therefore, we hypothesized that liposomal clodronate would be a useful agent for treating AIHA. We tested this hypothesis in a mouse model of AIHA in which animals were given either anti-RBC antibodies or pre-opsonized RBCs. In either case, liposomal clodronate substantially decreased RBC destruction. This drug formulation was rapidly effective within hours by first blocking and then depleting phagocytic macrophages, and its action lasted for 1 to 2 weeks. Thus, in AIHA, liposomal clodronate therapy may act like a temporary, medical splenectomy. As such, it may prove useful in situations where rapid response to therapy is critical or other medical therapies are inadequate.
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