EFFECTS OF IN-VIVO ADMINISTRATION OF STEM-CELL FACTOR ON THROMBOPOIESIS IN NORMAL AND IMMUNODEFICIENT MICE

Thrombocytopenia is an important clinical problem for many acquired im munodeficiency syndrome (AIDS) patients. Recently, the utility of reco mbinant cytokines in alleviating the hematopoietic complications of AI DS and AIDS therapy has been evaluated. The newly cloned cytokine stem cell factor (SCF) has been demonstrated to be a potent regulator of h ematopoietic progenitor cell proliferation. Therefore, we evaluated th e ability of SCF to alleviate thrombocytopenia caused by infection wit h LP-BM5 murine leukemia virus (mLV) in a murine model of AIDS (MAIDS) . In addition, we evaluated the effects of SCF on previously demonstra ted azidothymidine (AZT)-induced elevations of platelet counts. SCF wa s administered to normal or LP-BMS-infected C57BL/6 mice in combinatio n with oral AZT for up to I month and effects on platelet, megakaryocy te (MIC), and megakaryocyte colony-forming cell (CFU-MK) numbers were evaluated. SCF alone significantly increased the number of circulating platelets in thrombocytopenic MAIDS mice by 53%. SCF also significant ly elevated platelet levels by 29% in normal mice. AZT elevated platel et counts 100% in normal and 50% in MAIDS mice. AZT and SCF increased platelet counts in an additive manner. SCF alone was a potent inducer of splenic CFU-MK in both MAIDS and normal mice, increasing splenic CF U-MK 13- to IS-fold at day 15 as compared with untreated controls. By day 30, however, the numbers of splenic CFU-MK had returned to control levels. In infected mice, AZT alone increased the number of splenic C FU-MK. SCF administered to AZT-treated MAIDS mice did not further enha nce these increases. In contrast, in normal mice, AZT decreased spleni c CFU-MK numbers. In AZT-treated mice, SCF enhanced the numbers of spl enic CFU-MK 90-fold at day 8.In MAIDS mice, the number of bone marrow CFU-MK was significantly increased by SCF treatment at all time points . SCF significantly affected the total number of femoral CFU-MK in AZT -treated mice only at day 15. In normal mice, SCF or SCF and AZT in co mbination increased the total number of bone marrow CFU-MK five-fold a t day 8, but failed to induce changes in the total number of femoral C FU-MK after that. These results indicate that SCF elevates platelet le vels in both thrombocytopenic MAIDS and normal mice and profoundly aff ects CFU-MK proliferation. Combinations of SCF and AZT may be further explored to enhance the therapeutic effectiveness of these two drugs i n alleviating thrombocytopenia.