Treatment with liposome-encapsulated clodronate as a new strategic approach in the management of immune thrombocytopenic purpura in a mouse model.
Immune thrombocytopenic purpura (ITP) is an autoimmune disease related to the presence of elevated levels of platelet-associated immunoglobulin, or autoantibodies. In recent years the importance of macrophage Fc gamma receptors in the uptake of platelets in ITP has been confirmed. Although in patients with ITP the platelet destruction occurs in liver and spleen, in this present experimental mouse model the liver was the principal organ of sequestration of sensitized platelets. The uptake in the spleen, bone marrow, lung, and kidneys was negligible and not different from that in control animals. In addition, the trapped platelets did not return to circulation, and new cells derived from the platelet-storage pool or new thrombocytogenesis were necessary to restore the platelet count. The depletion of splenic and hepatic murine macrophages by liposome-encapsulated clodronate (lip-clod) was studied as a new strategy for ITP treatment. Lip-clod inhibits, in a dose-dependent manner, the antibody-induced thrombocytopenia. Moreover, lip-clod treatment rapidly restored (24 hours) the platelet count in thrombocytopenic animals to hematologic safe values, and despite additional antiplatelet antiserum treatment, mice were able to maintain this level of platelets at least up to 48 hours. The bleeding times in lip-clod-treated animals was not different from those in controls, demonstrating that the hemostasis was well controlled in these animals. The results presented in this study demonstrate that lip-clod treatment can be effective in the management of experimental ITP. (Blood. 2000;96:2834-2840)
Alves-Rosa
F
F
División Inmunología and Medicina Nuclear, Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina, Buenos Aires, Argentina.
Stanganelli
C
C
Cabrera
J
J
van Rooijen
N
N
Palermo
M S
MS
Isturiz
M A
MA
D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000503:physiopathology; D001760:Bleeding Time; D001792:Blood Platelets / Q000276:immunology / Q000473:pathology; D004002:Clodronic Acid / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004339:Drug Compounding; D004353:Drug Evaluation, Preclinical; D004906:Erythrocyte Count; D007106:Immune Sera / Q000633:toxicity; D007205:Indium Radioisotopes; D007958:Leukocyte Count; D008081:Liposomes; D008099:Liver / Q000503:physiopathology*; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D023421:Models, Animal; D009928:Organ Specificity; D009942:Organometallic Compounds; D015125:Oxyquinoline / Q000031:analogs & derivatives; D010976:Platelet Count; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D011817:Rabbits; D013154:Spleen / Q000503:physiopathology
D007106:Immune Sera; D007205:Indium Radioisotopes; D008081:Liposomes; D009942:Organometallic Compounds; D004002:Clodronic Acid; C032950:indium oxine; D015125:Oxyquinoline