Improved survival of lethally irradiated recipient mice transplanted with circulating progenitor cells mobilized by IL-8 after pretreatment with stem cell factor.
We have demonstrated previously that a single bolus-injection of interleukin (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) before IL-8-administration. The mobilized HPC were transplanted into lethally irradiated recipient mice to study the effects on survival. Male donor mice (age 8-12 weeks, weight 20-25 grams) were pretreated intraperitoneally (ip) with a fixed dose of 2.5 micrograms of either granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-3, stem cell factor (SCF), or saline administered twice daily for 2 to 4 days. Then a fixed dose of 30 micrograms of IL-8 was administered ip at various time intervals before harvesting blood, bone marrow, and spleen. Cell counts and numbers of colony-forming units granulocyte/macrophage (CFU-GM) of these organs were assessed. Donor mice pretreated with HGF for 2 days and subsequently injected with IL-8 showed an increase in the numbers of circulating CFU-GM per mL blood 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 +/- 15 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 interval). 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 mononuclear cells (PBMNC). Transplantation of 1.5 x 10(5) MNC obtained from donors pretreated with SCF for 2 days prior to IL-8 mobilization resulted in a significantly enhanced survival of 100% of the recipients, whereas recipients of PBM-NCs derived from donors treated with SCF only or IL-8 as a single injection had a survival rate at day 60 of only 50% and 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 conclude that pretreatment with SCF for 2 days improves the mobilizing effect induced by IL-8 and that transplantation of these cells enhances survival of lethally irradiated recipients.
Department of Hematology, Leiden University Hospital, The Netherlands.
L
L
Laterveer
J M
JM
Zijlmans
I J
IJ
Lindley
M S
MS
Hamilton
R
R
Willemze
W E
WE
Fibbe
D000818:Animals; D001854:Bone Marrow Cells; D002452:Cell Count / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D006085:Graft Survival / Q000528:radiation effects; D016209:Interleukin-8 / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011837:Radiation-Protective Agents / Q000494:pharmacology; D013154:Spleen / Q000166:cytology; D019089:Stem Cell Factor / Q000627:therapeutic use*; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology; D019172:Transplantation Conditioning; D014916:Whole-Body Irradiation
D016209:Interleukin-8; D011837:Radiation-Protective Agents; D019089:Stem Cell Factor