FACILITATED ENGRAFTMENT OF HUMAN HEMATOPOIETIC-CELLS IN SEVERE COMBINED IMMUNODEFICIENT MICE FOLLOWING A SINGLE INJECTION OF CL2MDP LIPOSOMES

Transplantation of normal and malignant human hematopoietic cells into severe combined immunodeficient (SCID) mice allows for evaluation of long-term growth abilities of these cells and provides a preclinical m odel for therapeutic interventions. However, large numbers of cells ar e required for successful engraftment in preirradiated mice due to res idual graft resistance, that may be mediated by cells from the mononuc lear phagocytic system. Intravenous (i.v.) injection of liposomes cont aining dichloromethylene diphosphonate (Cl2MDP) may eliminate mouse ma crophages in spleen and liver. In this study outgrowth of acute myeloi d leukemia (AML) cells and umbilical cord blood (UCB) cells in SCID mi ce conditioned with a single i.v. injection of Cl2MDP liposomes in add ition to sublethal total body irradiation (TBI) was compared to outgro wth of these cells in SCID mice that had received TBI alone. A two- to 10-fold increase in outgrowth of AML cells was observed in four cases of AML. Administration of 10(7) UCB cells reproducibly engrafted SCID mice that had been conditioned with Cl2MDP liposomes and TBI, whereas human cells were not detected in mice conditioned with TBI alone. As few as 2x10(4) purified CD34(+) UCB cells engrafted in all mice treate d with Cl2MDP liposomes. In SCID mice treated with macrophage depletio n unexpected graft failures were not observed. Histological examinatio n of the spleen showed that TBI and Cl2MDP liposomes i.v. resulted in a transient elimination of all macrophage subsets in the spleen, where as TBI had a minor effect. Cl2MDP liposomes were easy to use and their application was not associated with appreciable side-effects. Cl2MDP liposome pretreatment in combination with TBI allows for reproducible outgrowth of high numbers of human hematopoietic cells in SCID mice.