IMPROVED SURVIVAL OF LETHALLY IRRADIATED RECIPIENT MICE TRANSPLANTED WITH CIRCULATING PROGENITOR CELLS MOBILIZED BY IL-8 AFTER PRETREATMENTWITH STEM-CELL FACTOR

We have demonstrated previously that a single bolus-injection of inter leukin (IL)-8 induces instant mobilization of hematopoietic progenitor cells (HPC) in mice and primates. To further improve the mobilization of HPC, we treated mice with hematopoietic growth factors (HGF) befor e IL-8-administration. The mobilized HPC were transplanted into lethal ly irradiated recipient mice to study the effects on survival. Male do nor mice (age 8-12 weeks, weight 20-25 grams) were pretreated intraper itoneally (ip) with a fixed dose of 2.5 mu g of either granulocyte col ony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulat ing factor (GM-CSF), IL-3, stem cell factor (SCF), or saline administe red twice daily for 2 to 4 days. Then a fixed dose of 30 mu g of IL-8 was administered ip at various time intervals before harvesting blood, bone marrow, and spleen. Cell counts and numbers of colony-forming un its granulocyte/macrophage (CFU-GM) of these organs were assessed. Don or mice pretreated with HGF for 2 days and subsequently injected with IL-8 showed an increase in the numbers of circulating CFU-GM per mt bl ood from 168 +/- 98 to 402 +/- 201 (mean +/- SD, CFU-GM/mL blood) when GM-CSF was used, 314 +/- 133 to 2502 +/- 513 with G-CSF, and 27 +/- 1 5 to 524 +/- 339 with SCF compared with saline-pretreated controls (28 +/- 17 to 462 +/- 335 CFU-GM/mL blood, mean +/- SD; n=42 and 40 per i nterval). Donor-mice pretreated for 4 days with IL-3 or GM-CSF showed an increase in the numbers of circulating HPC from 62 +/- 52 to 368 +/ - 118 and 859 +/- 387 to 1034 +/- 421, respectively (CFU-GM/mL, mean /- SD, n=4 per group). Lethally irradiated (8.5 Gy) female Balb/c mice were then injected with decreasing numbers of peripheral blood mononu clear cells (PBMNC). Transplantation of 1.5x10(5) MNC obtained from do nors pretreated with SCF for 2 days prior to IL-8 mobilization resulte d in a significantly enhanced survival of 100% of the recipients, wher eas recipients of PBMNCs derived from donors treated with SCF only or IL-8 as a single injection had a survival rate at day 60 of only 50% a nd 60% respectively. When equal numbers of IL-8-mobilized MNCs from G- CSF, GM-CSF, or IL-3 pretreated donors were transplanted into lethally irradiated recipients, no such survival-advantage was observed. We co nclude that pretreatment with SCF for 2 days improves the mobilizing e ffect induced by IL-8 and that transplantation of these cells enhances survival of lethally irradiated recipients.