The severe combined immunodeficient-human peripheral blood stem cell (SCID-huPBSC) mouse: a xenotransplant model for huPBSC-initiated hematopoiesis.
Mononuclear cells (MNCs) containing peripheral blood stem cells (PBSCs) were obtained from solid-tumor patients undergoing mobilizing chemotherapy followed by granulocyte colony-stimulating factor for PBSC transplantation-supported dose-intensified anticancer chemotherapy and were transplanted into unconditioned "nonleaky" young severe combined immunodeficient mice. Multilineage engraftment was shown by flow cytometry and immunocytochemistry using monoclonal antibodies to various human cell surface antigens as well as identification of human immunoglobulin in murine sera. Within a dose range of MNCs suitable for transplantation (10 to 36 x 10(6) cells/graft) the number of CD34+ cells injected (optimal at > 0.7 x 10(6)/graft) determined the yield of human cells produced in recipient animals. Engraftment of hu PBSC preparations resulted in prolonged generation of physiologic levels of human cytokines including interleukin-3 (IL-3), IL-6, and granulocyte-macrophage colony-stimulating factor, which were detectable in the murine blood over a period of at least 4 months. In vivo survival of immature human progenitor cells was preserved even 9 months after transplantation. Because human IL-3 is known to stimulate early hematopoiesis, a rat fibroblast cell line was stably transfected with a retroviral vector carrying the human IL-3 gene and cotransplanted subcutaneously as additional source of growth factor. Cotransplants of this cell line producing sustained in vivo levels of circulating human IL-3 for at least 12 weeks significantly accelerated the process of engraftment of huPBSC and spurred the spread of mature human cells to the murine spleen, liver, thymus, and peripheral blood. Cotransplants of allogeneic human bone marrow stromal cells derived from long-term cultures resulted in a comparable--though less prominent--support of engraftment.
Goan
S R
SR
Department of Medical Oncology and Applied Molecular Biology, University Clinics Rudolf Virchow, Robert-Rössle Cancer Center, Free University of Berlin, Germany.
Fichtner
I
I
Just
U
U
Karawajew
L
L
Schultze
W
W
Krause
K P
KP
von Harsdorf
S
S
von Schilling
C
C
Herrmann
F
F
D000328:Adult; D000818:Animals; D000917:Antibody Formation; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D001761:Bleomycin / Q000008:administration & dosage / Q000494:pharmacology; D016026:Bone Marrow Transplantation; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy; D002460:Cell Line; D002678:Chimera; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology; D015251:Epirubicin / Q000008:administration & dosage / Q000494:pharmacology; D005047:Etoposide / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000637:transplantation*; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology; D006085:Graft Survival; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006410:Hematopoiesis / Q000502:physiology*; D016298:Hematopoietic Cell Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage / Q000494:pharmacology; D007377:Interleukin-3 / Q000096:biosynthesis; D008221:Lymphoid Tissue / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID / Q000502:physiology*; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy; D051381:Rats; D016511:Severe Combined Immunodeficiency / Q000503:physiopathology; D013736:Testicular Neoplasms / Q000097:blood / Q000188:drug therapy; D014183:Transplantation, Heterologous
D016298:Hematopoietic Cell Growth Factors; D007377:Interleukin-3; D001761:Bleomycin; D016179:Granulocyte Colony-Stimulating Factor; D015251:Epirubicin; D005047:Etoposide; D003520:Cyclophosphamide; D002945:Cisplatin; D005472:Fluorouracil; D007069:Ifosfamide